Clinical trial NCT02128958
Conditions: Hepatocellular Carcinoma
Keywords: Hepatocellular Carcinoma Child-Pugh Class B Cirrhosis
Sponsor: Can-Fite BioPharma
Start date: 2014-09-01; Completion date: 2021-12-31
Enrollment: 78 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, randomized, double-blind, placebo-controlled clinical trial in subjects with advanced HCC and CPB cirrhosis whose disease has progressed while taking 1 prior systemic drug therapy for HCC.

Detailed description:
The trial will evaluate the efficacy and safety of CF102 as compared to placebo. Subjects will be randomly assigned in a 2:1 ratio to treatment with oral doses of either CF102 25 mg or matching placebo administered twice daily (BID) for consecutive, 28-day cycles. Subjects will be evaluated regularly for safety. Tumor imaging will be performed every 8 weeks. Treatment will continue until the subject experiences unacceptable drug-related intolerability. Subjects will return for a follow-up visit 28 days after completion of the last dose of study drug, and every attempt will be made to obtain survival data on all randomized subjects. Subjects who discontinue will be followed indefinitely for survival status. The trial will continue until 75 deaths have been recorded.

Arms: arm 1: orally q12h arm 2: orally q12h
Interventions: intervention 1: CF102 intervention 2: Placebo
Intervention descriptions: intervention 1: orally q12h intervention 2: orally q12 hours

Protocol documents:
Prot_000.pdf: 
 
1 
CLINICAL STUDY PROTOCOL 
Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Study of the Efficacy and Safety of CF102 in the Second-Line 
Treatment of Advanced Hepatocellular Carcinoma in Subjects 
with Child-Pugh Class B Cirrhosis 
Test Drug: 
CF102 
Protocol Identification: 
CF102-201HCC 
Sponsor: 
Can-Fite BioPharma, Ltd. 
10 Bareket Street, Petach Tikva, Israel 
+972 3 924 1114 
Compliance Statement: 
The trial will be conducted in accordance with standards of Good 
Clinical Practice, as defined by the International Conference on 
Harmonisation and all applicable national and local regulations. 
Date of Protocol: 
07 January 2014 
Date of Amendments 
Amendment #1, 16 June 2014 
Amendment #2, 3 October 2014 
Amendment #3, 21 October 2015 
Amendment #4, 21 September 2018 
Amendment #5, 6 November 2018 
 
 
 
Michael H. Silverman, MD 
Medical Monitor 
 
 
 
6 November 2018 
Signature 
Date 
Prof. Pnina Fishman, PhD 
Chief Executive Officer 
 
 
 
6 November 2018 
Signature 
Date 
 
 
 
Confidentiality Statement 
The information contained within this document is confidential and may not be use, divulged, published, 
or otherwise disclosed without the prior written consent of Can-Fite BioPharma, Ltd. 
 


Can-Fite BioPharma, Ltd. 
Protocol CF102-201HCC, Amendment 5 
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6 November 2018 
 
2 
INVESTIGATOR AGREEMENT 
 
 
Protocol Title: 
CF102-201HCC: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the 
Efficacy and Safety of CF102 in the Second-Line Treatment of Advanced Hepatocellular 
Carcinoma in Subjects with Child-Pugh Class B Cirrhosis 
 
Investigator Statement: 
I have received and completely reviewed the above-named protocol, including all appendices 
and amendments. As Investigator, I agree to conduct the trial in accordance with all stipulations 
of the protocol and in accordance with 21 CFR Part 50, ICH Guidelines for Good Clinical 
Practices (GCP), and the Declaration of Helsinki. 
 
 
Investigator 
Signature: 
 
 
Investigator 
Name (print): 
 
 
 
Date:  
 
Investigator 
Address: 
 
 
 
 
Institution  
Telephone No.: 
 
 
 
 
 
Institution  
Fax No.: 
 
 
 
 
 
Signature on this page assures Can-Fite BioPharma, Ltd. that, to the best of the Investigator’s 
knowledge, the affiliated IRB/EC operates in accordance with applicable local and national 
regulations, and that the Investigator understands and agrees to abide by all regulatory 
obligations and ICH GCP guidelines while conducting this clinical investigation. 
 
Once signed, the original of this form should be detached from the protocol and returned to the Sponsor. 
(Please retain a copy for your files) 
 


Can-Fite BioPharma, Ltd. 
Protocol CF102-201HCC, Amendment 5 
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6 November 2018 
 
3 
TRIAL CONTACT INFORMATION 
 
 
Serious and Unexpected Adverse Events 
Any death, serious adverse event (SAE), or suspected unexpected serious adverse reaction 
(SUSAR) occurring in a subject while receiving study drug or within 30 days of receiving study 
drug, even though the event may not appear to be study drug related, must be promptly reported 
(within 24 hours) by telephone, fax, or e-mail to the Sponsor (or designee). 
Unless otherwise instructed, SAE and SUSAR reports are to be submitted by fax to: 
Medical Monitor: 
Study Director: 
Michael H. Silverman, MD, FACP 
BioStrategics Consulting Ltd. 
51 Intrepid Circle 
Marblehead MA 01945, USA 
Telephone: +1 781-631-8596 
Fax: +1 781-989-3227 
Email: msilverman@biostrategics.com 
Zivit Harpaz 
Can-Fite BioPharma, Ltd. 
10 Bareket St. 
Petach Tikva, Israel 
Telephone: +972 3 924 1114 
Fax: +972 3 924 9378 
Email: zivit@canfite.co.il 
 
For urgent medically-related questions, contact the Medical Monitor. On weekends, holidays, 
and after business hours, you may also call 781-639-1349 and leave a message. 


Can-Fite BioPharma, Ltd. 
Protocol CF102-201HCC, Amendment 5 
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6 November 2018 
 
4 
1.0 
SYNOPSIS 
Sponsor: 
Can-Fite BioPharma, Ltd. 
Product: 
CF102 
Study Title: 
CF102-201HCC: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the 
Efficacy and Safety of CF102 in the Second-Line Treatment of Advanced Hepatocellular 
Carcinoma in Subjects with Child-Pugh Class B Cirrhosis 
Estimated Number of Trial Centers: 
Multicenter, up to 22-24 sites in 5 countries 
Phase of Development: 2 
Objectives: 
The primary objective of this trial is to: 
• 
Evaluate the efficacy of orally administered CF102 25 mg twice daily (BID) as compared to 
placebo, as determined by Overall Survival (OS), when used as second-line therapy in 
subjects with advanced hepatocellular carcinoma (HCC) and Child-Pugh Class B (CPB) 
cirrhosis. 
The secondary objectives of this trial are to: 
• 
Evaluate other indicators of efficacy of CF102 as compared to placebo, including time to 
progression (TTP), progression-free survival (PFS), objective response (OR) rate, and 
disease control (DC) rate in this population; 
• 
Explore exposure-response relationships using sparse pharmacokinetic (PK) sampling; 
• 
Characterize the safety profile of CF102 in subjects with advanced HCC and CPB cirrhosis; 
• 
Characterize the effects of CF102 on laboratory parameters associated with viral hepatitis, 
hepatic dysfunction, and cirrhosis; and 
• 
Explore the relationship between white blood cell (WBC) adenosine A3 receptor (A3AR) 
expression and clinical response. 
Methods: 
This is a multicenter, randomized, double-blind, placebo-controlled clinical trial in subjects with 
advanced HCC and CPB cirrhosis who did not tolerate prior sorafenib therapy or experienced 
disease progression on prior sorafenib therapy. The trial will evaluate the efficacy and safety of 
CF102 as compared to placebo. Subjects will be randomly assigned in a 2:1 ratio to treatment 
with oral doses of either CF102 25 mg or matching placebo administered BID for consecutive, 
28-day cycles. Subjects will be evaluated regularly for safety, and will undergo sparse PK 


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sampling to assess the PK profile of CF102 and to explore exposure-response relationships. 
Tumor imaging will be performed every 8 weeks. Treatment will continue until the subject 
experiences unacceptable drug-related intolerability (Section 8.2). Subjects will return for a 
follow-up visit 28 days after completion of the last dose of study drug, and every attempt will be 
made to obtain survival data on all randomized subjects. Subjects who discontinue will be 
followed indefinitely for survival status. 
Once the requisite number of events has occurred and the blind is opened for analysis of the trial 
results, any surviving subjects who remain on blinded drug will be offered the opportunity to 
continue dosing with open-label CF102 25 mg BID indefinitely, following the protocol-specified 
schedule of events (Table 1–2). 
Number of Subjects Planned: 
Approximately 78 subjects will be enrolled and randomized in a 2:1 ratio to receive either CF102 
or matching placebo. 
Diagnosis and Main Criteria for Inclusion: 
DB Portion of the Trial 
Inclusion Criteria: 
1. 
Males and females at least 18 years of age. 
2. 
Diagnosis of HCC: 
□ 
For subjects without underlying cirrhosis at the time of diagnosis, diagnosis of HCC 
documented by cytology and/or histology. 
□ 
For subjects with underlying cirrhosis at the time of diagnosis, diagnosis of HCC 
established according to the American Association for the Study of Liver Diseases 
Practice Guideline algorithm (Appendix E). 
3. 
HCC is advanced, i.e., treatment-refractory or metastatic, and no standard therapies are 
expected to be curative. 
4. 
Receipt of prior sorafenib therapy for at least 3 weeks and withdrawal from treatment due 
either to intolerability or to radiographic evidence of disease progression. If treatment was 
withdrawn due to intolerability manifested as a Grade 3 or 4 event by National Cancer 
Institute Common Toxicity Criteria for Adverse Events (CTCAE v4.0), less than 3 weeks 
of continuous prior administration prior to withdrawal is acceptable (see also Exclusion 
Criterion #3). 
5. 
Prior sorafenib treatment was discontinued for at least 2 weeks prior to the Baseline Visit. 
6. 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2 (Appendix B). 
7. 
Cirrhosis classified as Child-Pugh Class B (Appendix C). 


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8. 
The following laboratory values must be documented within 3 days prior to the first dose 
of study drug: 
□ 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
□ 
Platelet count ≥ 75 × 109/L 
□ 
Serum creatinine ≤ 2.0 mg/dL 
□ 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × the 
upper limit of normal (ULN) 
□ 
Total bilirubin ≤ 3.0 mg/dL 
□ 
Serum albumin ≥ 2.8 g/dL 
□ 
Prothrombin time (PT) no greater than 6 seconds longer than control. 
9. 
Life expectancy of ≥ 6 weeks. 
10. For women of childbearing potential, negative serum pregnancy test result. 
11. Provide written informed consent to participate. 
12. Willing to comply with scheduled visits, treatment plans, laboratory assessments, and other 
trial-related procedures. 
Exclusion Criteria: 
1. 
Receipt of no, or of > 1, prior systemic drug therapies for HCC. 
2. 
Receipt of systemic cancer therapy, immunomodulatory drug therapy, immunosuppressive 
therapy, or corticosteroids > 20 mg/day prednisone or equivalent within 14 days prior to the 
Baseline Visit or concurrently during the trial. 
3. 
Presence of an acute or chronic toxicity of prior chemotherapy that has not resolved to 
≤ Grade 1, as determined by CTCAE v 4.0. 
4. 
Locoregional treatment within 4 weeks prior to the Baseline Visit. 
5. 
Major surgery or radiation therapy within 4 weeks prior to the Baseline Visit. 
6. 
Use of any investigational agent within 4 weeks prior to the Baseline Visit. 
7. 
Child-Pugh Class A or C cirrhosis, or hepatic encephalopathy. 
8. 
Occurrence of esophageal or other gastrointestinal hemorrhage requiring transfusion within 
4 weeks prior to the Baseline Visit. 
9. 
Uncontrolled or clinically unstable thyroid disease, per judgment of the Principal 
Investigator. 
10. Active bacterial, viral, or fungal infection requiring systemic therapy or operative or 
radiological intervention. 
11. Known human immunodeficiency virus- or acquired immunodeficiency syndrome-related 
illness. 


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12. Liver transplant. 
13. Active malignancy other than HCC. 
14. Uncontrolled arterial hypertension or congestive heart failure (New York Heart Association 
Classification 3 or 4) (Appendix B). 
15. Angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass 
graft surgery, transient ischemic attack, or pulmonary embolism within 3 months prior to 
initiation of study drug. 
16. History of or ongoing cardiac dysrhythmias requiring treatment, atrial fibrillation of any 
grade, or persistent prolongation of the QTc (Fridericia) interval to > 450 msec for males or 
> 470 msec for females. 
17. Pregnant or lactating female. 
18. Women of childbearing potential, unless they agree to use dual contraceptive methods 
which, in the opinion of the Investigator, are effective and adequate for the subject’s 
circumstances while on study drug. 
19. Men who partner with a woman of childbearing potential, unless they agree to use effective, 
dual contraceptive methods (i.e., a condom, with female partner using oral, injectable, or 
barrier method) while on study drug and for 3 months afterward. 
20. Any severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality 
that may increase the risk associated with trial participation or study drug administration; 
may interfere with the informed consent process and/or with compliance with the 
requirements of the trial; or may interfere with the interpretation of trial results and, in the 
Investigator’s opinion, would make the subject inappropriate for entry into this trial. 
Eligibility Criteria for Open Label 
• 
The subject signed the ICF for the Open Label treatment. 
• 
The subject received double blind treatment with CF102/placebo and is still taking the 
investigational medication when Amendment 5 is approved. 
Test Product, Dose, and Mode of Administration: 
CF102 is a small molecule agonist of the A3AR. Study drug will be supplied in child- and 
tamper-resistant bottles as hard capsules containing either 25 mg of CF102 or matching placebo. 
CF102 or placebo will be self-administered orally BID on an empty stomach (1 hour before or 
2 hours after meals) beginning on Day 1 of the trial and thereafter at approximately the same 
times each day of the 28-day cycle. 
Dosing Interruptions and Reductions: 
In the case of any Grade 3 toxicity by CTCAE v4.0 judged by the Principal Investigator to be at 
least “possibly” drug-related, the dose of study drug will be interrupted for up to 7 days. If 


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toxicity does not resolve to Grade ≤ 1 within 7 days, the subject will be discontinued from 
treatment. If toxicity does resolve to Grade ≤ 1 within 7 days, dosing will be resumed at the 
decreased dose of 1 capsule per day. In the case of any Grade 4 toxicity by CTCAE v4.0 judged 
by the Principal Investigator to be at least “possibly” drug-related, the dose of study drug will be 
withdrawn permanently. 
Only 1 dose reduction will be allowed. If a Grade 3 or 4 toxicity judged by the Principal 
Investigator to be at least “possibly” drug-related occurs upon re-challenge at the reduced dose, 
study drug dosing will be withdrawn permanently. 
Duration of Treatment: 
Each treatment cycle will be 28 days of twice daily dosing. Treatment will continue until the 
subject experiences unacceptable drug-related intolerability. 
Once the requisite number of events has occurred and the blind is opened for analysis of the trial 
results, any surviving subjects who remain on blinded drug will be offered the opportunity to 
continue dosing with open-label CF102 25 mg BID indefinitely, following the protocol-specified 
schedule of events (Table 1–2). 
Criteria for Evaluation: 
Efficacy: 
The primary efficacy endpoint will be OS, defined as the number of days from first dose to death 
due to any cause. Secondary endpoints to be evaluated are TTP, PFS, OR rate consisting of 
Complete Response (CR) or Partial Response (PR) for subjects who enter the trial with 
measurable disease by RECIST v1.1, and DC rate which includes both subjects who experience 
OR as well as those who experience Stable Disease (SD). Survival status will be assessed 
continuously. Tumor status will be assessed at the Pre-Study Visit and every 8 weeks thereafter 
(i.e., at the end of even-numbered cycles) by computed tomography (CT) scan or magnetic 
resonance imaging (MRI) according to RECIST v1.1 (Appendix A, [Eisenhauer 2009 as 
modified by Santoro 2013]). 
Alpha-fetoprotein (AFP) levels will be assessed at baseline and every 4 weeks thereafter on 
Day 1 of each subsequent cycle. 
Laboratory parameters associated with hepatic dysfunction and cirrhosis, such as serum ALT, 
AST, bilirubin, and albumin levels, prothrombin time (PT), and International Normalized Ratio 
(INR), will be assessed every cycle. Where applicable, viral load measurements will be 
performed every odd-numbered cycle. WBC A3AR expression will be assessed at baseline and, 
unless waived by the Sponsor, every odd-numbered cycle (at selected sites only). 


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Safety: 
Assessments of adverse events (AEs) will include characterization of the type, incidence, 
severity (graded by CTCAE v 4.0), seriousness, and relationship to treatment. Changes in vital 
signs, laboratory parameters including thyroid functions, electrocardiograms (ECG), physical 
examinations, and ECOG PS from baseline will be assessed. 
Pharmacokinetics: 
CF102 concentrations will be determined from EDTA plasma samples obtained on Day 1 of 
Cycles 1 and 2, as well as from trough samples on Days 8 and 15 of Cycle 1. A composite PK 
profile following the morning dose of the BID regimen will be generated for subjects receiving 
CF102 treatment. 
Statistical Analysis: 
Sample Size: 
Approximately 78 subjects will be enrolled during an accrual period estimated to be 
approximately 78 weeks (18 months) in duration and randomized to either CF102 or placebo 
using a 2:1 randomization. Assuming a hazard ratio of 0.5, 75 events will provide 80% power for 
the logrank test at level 0.05. 
General Considerations: 
Time to event variables will be summarized using the number observed, number censored, 
median, and 25th and 75th percentiles from Kaplan-Meier curves. Continuous variables will be 
summarized using number of subjects (n), mean, median, standard deviation, minimum, and 
maximum. Categorical variables will be summarized using frequencies and percentages. 
Efficacy Analyses: 
Between-treatment comparisons with respect to OS, TTP, and PFS will be performed using 
logrank tests, with Cox’s proportional hazards regression model used for secondary analyses to 
assess the impact of covariates. Tumor lesion measurements and changes from baseline will be 
summarized by cycle and treatment. Objective response rates and DC rates will be presented and 
between-treatment comparisons will be performed using the normal approximation to the 
binomial distribution by treatment for each even-numbered cycle. Between-treatment 
comparisons with respect to AFP will be performed using Analysis of Covariance (ANCOVA) 
with the baseline value used as a covariate and frequencies of subjects with AFP levels <20, 20-
200, or >200 ng/mL will be presented by treatment for each cycle. 
Pharmacokinetic Analyses: 
PK analysis will include population PK analysis based on sparse sampling, and the estimation of 
Cmax, Cmin and AUC(0-12h) on Day 1 of Cycles 1 and 2; and trough plasma levels on Days 8 and 15 


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of Cycle 1. Exploratory analyses will be performed to evaluate the relationship between these PK 
parameters and WBC A3 receptor expression and clinical responses to CF102. 
Safety Analyses: 
Safety data analysis will be conducted on all subjects receiving at least 1 dose of CF102 or 
matching placebo. The number and percentage of subjects experiencing 1 or more AEs will be 
summarized by treatment group, relationship to study drug, and severity. AEs will be coded 
using Medical Dictionary for Regulatory Activities (MedDRA™) terminology. Listings of 
subjects who experienced dosing interruptions and dose reductions, withdrawal due to an AE, 
serious AEs and/or death will be presented. Laboratory parameters, other than Liver Chemistry 
Tests (see below), INR, and viral load, will be summarized using descriptive statistics and data 
listings of clinically significant abnormalities. Liver Chemistry Tests, INR, and viral load will be 
presented as exploratory efficacy variables. Vital signs, ECOG PS, physical examination, and 
ECG data will be summarized by changes from baseline values for each treatment group using 
descriptive statistics. 
Exploratory Analyses: 
Certain laboratory parameters associated with hepatic dysfunction and cirrhosis will be 
examined. These include: Chemistry (bilirubin [direct and total], ALT, AST, and albumin, 
referred to collectively as “Liver Chemistry Tests”); INR; and viral load. These parameters will 
be summarized using descriptive statistics and clinically significant abnormalities will be listed. 
Additionally, between-treatment comparisons will be performed using ANCOVA with the 
baseline value used as a covariate. The relationship between WBC A3AR expression and clinical 
response will be assessed by providing the counts and percentages for Overall Response by 
Change from Baseline (CFB) in A3AR expression categorized as less than or at least the median 
by treatment at each visit. 
 


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Table 1–1: 
Schedule of Events for Double Blind Portion of the Trial 
Trial Procedures  
Pre-Study 
(-28 Days) 
Cycle 1 
Subsequent Cycle 
End of Study/End 
of Dosing (EOS)1 
Follow-up 
(28 ± 3 
Days Post 
EOS) 
Day 1 
Baseline 
Days 8 and 15 
±2 Days 
Day 1 
±2 Days 
Day 15 
±2 Days 
Day 1 
± 2 Days 
Medical and disease history 
X 
 
 
 
 
 
 
Physical examination 
Xa 
Xa,c 
Xb 
Xb 
Xb 
Xa 
Xb 
Inclusion/exclusion criteria 
X 
X  
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Body weight 
X 
Xc 
 
X 
 
X 
X 
Vital signsd  
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory testinge 
X 
Xc 
X 
X 
X 
X 
X 
T3. T4, TSH 
X 
X 
 
X 
 
X 
X 
ECG f 
X 
X 
Xf 
X 
X 
X 
X 
Pregnancy test (serum)g 
X 
Xc 
 
X 
 
X 
X 
ECOG PSg 
X 
Xc 
 
X 
 
X 
 
α-fetoprotein (AFP) 
 
X 
 
X 
 
X 
X 
WBC A3AR sample 
 
X 
 
Xh 
 
 
 
PK samples  
 
X k 
X k 
X k 
 
 
 
Hepatitis B/C virus serology 
X 
 
 
 
 
 
 
Hepatitis B/C viral load (if seropositive) 
 
X 
 
X i 
 
X i 
 
Tumor imaging for RECIST 
Xj 
 
 
Xj 
 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
Dispense study drug supplies 
 
X 
 
X 
 
 
 
Review treatment compliance 
 
X 
X 
X 
X 
X 
 


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Trial Procedures  
Pre-Study 
(-28 Days) 
Cycle 1 
Subsequent Cycle 
End of Study/End 
of Dosing (EOS)1 
Follow-up 
(28 ± 3 
Days Post 
EOS) 
Day 1 
Baseline 
Days 8 and 15 
±2 Days 
Day 1 
±2 Days 
Day 15 
±2 Days 
Day 1 
± 2 Days 
a. 
Complete PE performed at the Pre-Study (and/or the Baseline Visit if performed > 3 days prior to first dose) and End of Study/End of Dosing (EOS) visits. 
b. 
Symptom-directed examination. 
c. 
If Pre-Study assessment was performed ≤ 3 days prior to the Baseline Visit, assessments do not need to be repeated. 
d. 
Temperature, pulse, respiration, blood pressure at: Pre-Study; pre-dose at all visits; at 1, 2, 3, 4h (± 5 min), 6 and 8h (± 10 min) post-dose on Cycle 1 Day 1 and at Follow-up. 
e. 
See list of parameters in Section 9.2.8 and Appendix D. 
f. 
ECG at Pre-Study; pre-dose at all visits; and at 2, 4, and 6h (± 10 min) post-dose on Cycle 1 Days 1 and 8; and at Follow-up. 
g. 
Performed at Pre-Study, prior to the first dose, Day 1 of each cycle, and at Follow-up. 
h. 
Day 1 of odd-numbered cycles, unless waived by the Sponsor (selected sites only). 
i. 
For subjects with measurable viral load at the Baseline Visit; on Day 1 of odd-numbered cycles only and at EOS. 
j. 
CT scan or MRI at Pre-Study, the end of Cycle 2, and at the end of subsequent even-numbered cycles. For trial eligibility purposes, a scan performed ≤ 21 days prior to the 
Pre-Study Visit may be used (allowed time window is of -7days/+1 day with respect to day 28 of each even numbered cycles; if performed at +1 day after day 28, CT/MRI 
scan must be performed before administration of the morning dose of that day). 
k. 
Sparse sampling on Day 1 of Cycles 1 and 2 only. Pre-dose trough sample on Cycle 1 Days 8 and 15 only. See Table 10–1 for PK sampling time points. 
l. 
End of Study visit timeframe is of 2 days since the last administered dose of IMP/matching Placebo. 
 
 


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Table 1–2: 
Schedule of Events for Open Label (OL) Treatment 
Trial Procedures  
OL Cycle 1 
Subsequent OL Cycle 
OL End of 
Study/End of 
Dosing (EOS) j 
OL Follow-
up (28 ± 3 
Days Post 
EOS) 
Day 1 
Baseline 
Days 8 and 15 
± 2 Days 
Day 1 
± 2 Days 
Day 15 
± 2 Days 
Day 1 
± 2 Days 
Physical examination 
Xb 
Xb 
Xb 
Xb 
Xa 
Xb 
Eligibility criteria for OL 
X  
 
 
 
 
 
Informed consent for OL 
X 
 
 
 
 
 
Body weight 
X 
 
X 
 
X 
X 
Vital signs c 
X 
X 
X 
X 
X 
X 
Clinical laboratory testing d 
X 
X 
X 
X 
X 
X 
T3, T4, TSH 
X 
 
X 
 
X 
X 
ECG e 
X 
X 
X 
X 
X 
X 
Pregnancy test (serum) f 
X 
 
X 
 
X 
X 
ECOG PS f 
X 
 
X 
 
X 
 
α-fetoprotein (AFP) 
X 
 
X 
 
X 
X 
WBC A3AR sample 
X 
 
Xg 
 
 
 
Hepatitis B/C viral load (if seropositive) 
X 
 
X h 
 
X h 
 
Tumor imaging for RECIST 
 
 
X i 
 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Dispense study drug supplies 
X 
 
X 
 
 
 
Review treatment compliance 
X 
X 
X 
X 
X 
 
a. 
Complete PE performed at Open Label (OL) End of Study/OL End of Dosing (EOS) visits. 
b. 
Symptom-directed physical examination. 


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c. 
Temperature, pulse, respiration, blood pressure performed at the following times: pre-dose at all visits; at 1, 2, 3, 4h (± 5 min), 6 and 8h (± 10 min) post-dose on OL Cycle 1 
Day 1 and at OL Follow-up. 
d. 
See list of parameters in Section 9.2.8 and Appendix D. 
e. 
ECG at pre-dose at all visits; and at 2, 4, and 6h (± 10 min) post-dose on OL Cycle 1 Days 1 and 8; and at OL Follow-up. 
f. 
Performed pre-dose on Day 1 of each OL cycle, and at OL Follow-up. 
g. 
Day 1 of odd-numbered cycles, unless waived by the Sponsor (selected sites only). 
h. 
For subjects with measurable viral load at the Baseline Visit; on Day 1 of OL odd-numbered cycles only and at OL EOS. 
i. 
CT scan or MRI at the end of OL even-numbered cycles. If performed at +1 day after day 28, CT/MRI scan must be performed before administration of the morning dose of 
that day). 
j. 
End of Study OL visit timeframe is of 2 days since the last administered dose of IMP. 
 
 


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15 
2.0 
TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT ...............................................................................................2 
TRIAL CONTACT INFORMATION .........................................................................................3 
1.0 
SYNOPSIS ............................................................................................................................4 
LIST OF TABLES .......................................................................................................................19 
3.0 
LIST OF ABBREVIATIONS ............................................................................................20 
4.0 
INTRODUCTION ..............................................................................................................22 
4.1 
Overview of CF102 ..................................................................................................22 
4.2 
Previous Human Experience with CF102 ................................................................23 
4.2.1 
Phase 1 Trial in Normal Volunteers (CF102-101) .......................................23 
4.2.2 
Phase 1/2 Trial in Subjects with HCC (Study CF102-102HCC) .................24 
4.3 
Rationale for the Trial ..............................................................................................25 
4.4 
Rationale for Amendment 5 .....................................................................................25 
4.5 
Potential Risks and Benefits of Therapy ..................................................................26 
4.5.1 
Risks .............................................................................................................26 
4.5.2 
Potential Benefits .........................................................................................26 
5.0 
TRIAL OBJECTIVES .......................................................................................................27 
6.0 
INVESTIGATIONAL PLAN ............................................................................................27 
6.1 
Overall Trial Design and Plan Description ..............................................................27 
6.2 
Discussion of Trial Design Including the Choice of Control Group ........................28 
6.3 
Number of Subjects ..................................................................................................29 
6.4 
Duration of Trial .......................................................................................................29 
7.0 
SELECTION OF SUBJECTS ...........................................................................................29 
7.1 
Inclusion Criteria ......................................................................................................29 
7.2 
Exclusion Criteria .....................................................................................................30 
7.3 
Randomization and Blinding ....................................................................................31 
7.4 
Discontinuation from Dosing ...................................................................................32 
7.5 
Withdrawal from the Trial ........................................................................................33 
7.6 
Replacement of Subjects ..........................................................................................33 
7.7 
Eligibility Criteria for Open Label ...........................................................................33 
8.0 
TREATMENTS ..................................................................................................................33 
8.1 
Treatments Administered .........................................................................................33 
8.2 
Dose Modification ....................................................................................................34 


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8.3 
Study Drug Identification .........................................................................................34 
8.4 
Packaging and Labeling ...........................................................................................34 
8.5 
Study Drug Handling and Accountability ................................................................35 
8.6 
Treatment Compliance .............................................................................................35 
8.7 
Study Drug Disposal ................................................................................................36 
8.8 
Concomitant Medications and Supportive Care .......................................................36 
9.0 
EFFICACY AND SAFETY VARIABLES ASSESSED .................................................37 
9.1 
Trial Visits ................................................................................................................37 
9.2 
Trial Assessments .....................................................................................................38 
9.2.1 
Informed Consent .........................................................................................38 
9.2.2 
Demographics and Baseline Characteristics ................................................38 
9.2.3 
Concomitant Medications ............................................................................38 
9.2.4 
Adverse Event Assessments .........................................................................39 
9.2.5 
ECOG Performance Status ...........................................................................39 
9.2.6 
Vital Signs ....................................................................................................39 
9.2.7 
Physical Examination (PE) ...........................................................................39 
9.2.8 
Laboratory Assessments ...............................................................................39 
9.2.9 
WBC A3AR Expression ...............................................................................40 
9.2.10 
Electrocardiogram (ECG).............................................................................40 
9.2.11 
Tumor Assessment .......................................................................................40 
9.2.12 
Response Assessment ...................................................................................40 
9.2.13 
Pharmacokinetics Sampling .........................................................................41 
9.3 
Timing of Assessments ............................................................................................41 
9.3.1 
Pre-Study (Screening) Visit (-28 Days) .......................................................41 
9.3.2 
Cycle 1 Day 1 (Baseline) Visit .....................................................................41 
9.3.3 
Cycle 1 Day 8 and Day 15 Visits (± 2 days) ................................................42 
9.3.4 
Subsequent Cycles Day 1 Visit (± 2 days) ...................................................42 
9.3.5 
Subsequent Cycles Day 15 Visit (± 2 days) .................................................43 
9.3.6 
End of Study/End of Dosing (EOS) Visit (within 2 days of last dose) ........43 
9.3.7 
Follow-Up Visit (28 ± 3 days Post End of Dosing) .....................................44 
9.3.8 
Cycle 1 Day 1 OL Visit ................................................................................44 
9.3.9 
Cycle 1 Day 8 OL and Day 15 OL Visits (± 2 days) ...................................44 
9.3.10 
Subsequent Cycles Day 1 OL Visit (± 2 days) .............................................45 
9.3.11 
Subsequent Cycles Day 15 OL Visit (± 2 days) ...........................................45 


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9.3.12 
End of Study/End of Dosing (EOS) OL Visit (within 2 days of last 
dose) .............................................................................................................46 
9.3.13 
Follow-Up OL Visit (28 ± 3 days Post OL End of Dosing).........................46 
10.0 EFFICACY AND PHARMACOKINETICS ASSESSMENTS .....................................46 
10.1 
Response Assessments .............................................................................................46 
10.1.1 
Disease Classification ..................................................................................47 
10.1.2 
Diagnostic Imaging/Measurement of Target Lesions ..................................47 
10.1.3 
Response Assessment ...................................................................................47 
10.2 
Time to Event ...........................................................................................................47 
10.3 
Laboratory Assessments for Exploratory Efficacy ..................................................47 
10.3.1 
Liver Chemistry Tests ..................................................................................47 
10.3.2 
INR ...............................................................................................................48 
10.3.3 
Viral Load ....................................................................................................48 
10.4 
Pharmacokinetics Assessment ..................................................................................48 
10.4.1 
Sample Storage .............................................................................................48 
11.0 ASSESSMENT OF SAFETY ............................................................................................49 
11.1 
Safety Parameters .....................................................................................................49 
11.2 
Duration of Follow-Up .............................................................................................49 
11.3 
Safety Data Review During the Trial .......................................................................49 
11.4 
Adverse Event Definitions/Reporting Requirements ...............................................50 
11.4.1 
Adverse Event ..............................................................................................50 
11.4.2 
Suspected Adverse Reaction ........................................................................50 
11.4.3 
Adverse Reaction .........................................................................................50 
11.4.4 
Unexpected Adverse Event/Unexpected Suspected Adverse Reaction .......50 
11.5 
Serious Adverse Event Definitions/Reporting Requirements ..................................51 
11.5.1 
Serious Adverse Event or Serious Suspected Adverse Reaction .................51 
11.5.1.1 
Pregnancy ........................................................................................52 
11.5.2 
Serious and Unexpected Suspected Adverse Reaction ................................52 
11.6 
Recording Adverse Events .......................................................................................52 
11.7 
Determining Relationship of Adverse Events to Study Drug ..................................53 
11.7.1 
Unrelated ......................................................................................................53 
11.7.2 
Possibly Related ...........................................................................................53 
11.7.3 
Probably Related ..........................................................................................53 
11.7.4 
Related ..........................................................................................................54 
11.8 
Reporting Deaths and Other Serious Adverse Events ..............................................54 


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11.8.1 
Events to Be Reported and Timeframe ........................................................54 
11.8.2 
Events Excluded from Expedited Reporting to FDA ...................................54 
11.8.3 
Governing Regulatory Requirements ...........................................................55 
11.8.4 
Initial Information Provided by the Investigator ..........................................56 
11.8.5 
Follow-up Information .................................................................................56 
11.9 
SAE and SUSAR Review and Potential Impact on Trial Conduct ..........................56 
12.0 STATISTICAL METHODS AND PLANNED ANALYSES .........................................57 
12.1 
General Considerations ............................................................................................57 
12.2 
Sample Size Determination ......................................................................................58 
12.3 
Trial Populations ......................................................................................................58 
12.3.1 
Safety Population .........................................................................................58 
12.3.2 
Intent-to-Treat (ITT) Population ..................................................................58 
12.3.3 
Per Protocol (PP) Population ........................................................................58 
12.3.4 
Pharmacokinetic Population .........................................................................59 
12.4 
Data Analyses ...........................................................................................................59 
12.4.1 
Subject Accountability, Demographics, and Baseline Characteristics.........59 
12.4.2 
Efficacy Data ................................................................................................59 
12.4.3 
Safety Data ...................................................................................................60 
12.4.4 
Pharmacokinetics Data .................................................................................60 
13.0 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................60 
14.0 DOCUMENTATION AND INSPECTIONS ...................................................................61 
14.1 
Trial Monitoring .......................................................................................................61 
14.2 
Audits and Inspections .............................................................................................61 
15.0 ETHICAL AND LEGAL ISSUES ....................................................................................62 
15.1 
Ethical Conduct/Good Clinical Practice ..................................................................62 
15.2 
Institutional Review Board (IRB) and Ethics Committee (EC) ...............................62 
15.3 
Written Informed Consent ........................................................................................62 
15.3.1 
Update of Informed Consent ........................................................................63 
15.4 
Records and CRFs ....................................................................................................63 
15.5 
Modification of the Trial Protocol ...........................................................................64 
15.6 
Termination of the Trial ...........................................................................................64 
15.7 
Retention of Records ................................................................................................64 
16.0 PUBLICATION POLICY .................................................................................................65 
17.0 INVESTIGATOR RESPONSIBILITIES ........................................................................65 


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18.0 REFERENCES ...................................................................................................................67 
APPENDIX A: 
RECIST RESPONSE CRITERIA (V1.1) ....................................................70 
APPENDIX B: 
PERFORMANCE STATUS AND CARDIAC FUNCTION SCALES .....91 
APPENDIX C: 
CHILD-PUGH CLASSIFICATION OF SEVERITY OF LIVER 
DISEASE ........................................................................................................92 
APPENDIX D: 
CLINICAL LABORATORY TESTS ..........................................................93 
APPENDIX E: 
ALGORITHM FOR THE DIAGNOSIS OF HCC IN PATIENTS 
WITH UNDERLYING CIRRHOSIS ..........................................................94 
 
 
LIST OF TABLES 
Table 1–1: 
Schedule of Events for Double Blind Portion of the Trial.....................................11 
Table 1–2: 
Schedule of Events for Open Label (OL) Treatment .............................................13 
Table 4–1: 
Human Pharmacokinetic Parameters for CF102 ....................................................23 
Table 10–1: 
Timing of PK Samples ...........................................................................................48 
 
 


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3.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
A1AR 
subtype A1 of adenosine receptor 
A2AR 
subtype A2 of adenosine receptor 
A3AR 
subtype A3 of adenosine receptor  
AE 
adverse event 
AFP 
alpha-fetoprotein 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
Analysis of Covariance 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
β-hCG 
beta human chorionic gonadotropin 
BID 
twice daily 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
CPB 
Child-Pugh Class B cirrhosis 
CR 
complete response 
CRF 
case report form (which may refer to either paper or electronic versions) 
CRO 
Contract Research Organization 
CT 
computed tomography 
CTCAE 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
DC 
disease control rate (CR + PR + SD) 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
EOS 
end of study (end of dosing) 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HDPE 
high density polyethylene 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
ID 
identification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 


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Abbreviation 
Definition 
ITT 
intent to treat 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities  
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NF-κB 
nuclear factor kappa-light-chain-enhancer of activated B cells 
NYHA 
New York Heart Association 
OL 
Open label 
OR 
overall response rate (CR + PR) 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PE 
physical examination 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PO 
per os; oral(ly) 
PP 
Per Protocol 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors (version 1.1) 
RH 
relative humidity 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
serious adverse reaction 
SD 
stable disease 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
tmax 
time to Cmax 
TSH 
Thyroid stimulating hormone 
TTP 
time to progression 
ULN 
upper limit of normal 
WBC 
white blood cell 
Wnt 
group of signal transduction pathways 
 


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4.0 
INTRODUCTION 
4.1 
Overview of CF102 
CF102 is a synthetic ribose-based purine nucleoside with adenosine A3 receptor (A3AR) 
selectivity. CF102 selectivity for the A3AR is 4750-fold over A1AR and 1770-fold over A2AR. 
The A3AR is overexpressed in the tumor and in the peripheral blood mononuclear cells (PBMC) 
of patients with hepatocellular carcinoma (HCC). CF102, an A3AR agonist, inhibits tumor cell 
growth by inducing apoptosis of HCC cells via deregulation of the NF-κB and the Wnt signaling 
pathways (Olah, 1995; Bar-Yehuda, 2008; Fishman, 2002a; Fishman, 2002b; Fishman, 2003; 
Fishman, 2004; Madi, 2003; Ohana, 2003). A3AR agonists also stimulate natural killer cells in 
vivo, which further potentiates the antitumor activity of this class of compounds (Fishman 2000; 
Fishman 2002a; Fishman 2002b; Madi 2003; Bar-Yehuda, 2002; Bar-Yehuda, 2007). 
A3AR expression is also elevated in PBMC isolated from patients with hepatitis C viral (HCV) 
infections. HCV infection is associated with elevated and persistent NF-κB levels that inhibit 
apoptosis of the infected cells and lead to chronic HCV infection. The observation that CF102 
inhibits the replication of HCV in a culture system assay using human hepatoma Huh-7 cells 
transfected with HCV plasmid (JFH-1wt HCV) suggests that CF102 and other A3AR agonists 
may provide new therapies to treat HCV infections. In addition, CF102 acts as a protective agent 
against liver damage in acute hepatitis, ischemia and partial hepatectomy. These findings suggest 
a role for CF102 in preventing liver tissue damage associated with HCV infections and hepatitis. 
CF102 is a relatively low clearance compound in nonclinical species suggesting that there is little 
first pass effect and that absorption is the major limiting factor that dictates bioavailability. 
Plasma protein binding of CF102 is high, greater than 99% in all species. Studies with human 
hepatic microsomes indicate that drug-drug interactions related to CF102 inhibition of 
cytochrome p450 metabolism are unlikely to occur. 
CF102, given orally, induced a marked inhibitory effect on the growth of N1S1 HCC in an 
orthotopic model in rats. The drug was also efficacious in inhibiting the development of 
xenografted Hep-3B tumors inoculated subcutaneously in nude mice. 
CF102 has a favorable safety profile in nonclinical toxicology testing. In safety pharmacology 
studies, there were no adverse effects on respiratory or central nervous system parameters in 
monkeys. In monkeys, 60 mg/kg was associated with increased heart rate and 300 mg/kg caused 
increased heart weight in rats, likely secondary to increased heart rate. No toxicity was identified 
at 1000 or 300 mg/kg in 14-day toxicity studies in rats and monkeys, respectively. Higher doses 


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in monkeys were not tolerated and were associated with decreased food consumption and 
vomiting. 
CF102 was not genotoxic in the Ames, mouse lymphoma, and mouse micronucleus assays. 
4.2 
Previous Human Experience with CF102 
4.2.1 
Phase 1 Trial in Normal Volunteers (CF102-101) 
A Phase 1 randomized, dose-escalation trial was conducted in 25 male normal volunteers. Single 
doses of CF102 as high as 40 mg were not associated with intolerability, clinically important 
AEs, or changes in electrocardiograms (ECG) or laboratory assessments [data on file]. 
Absorption of CF102 following oral administration of 1, 3, 10, 20 or 40 mg CF102 was fairly 
slow, with Cmax observed at 2 to 6 hours after dosing. The median tmax ranged from 4 to 6 hours 
for the first 4 cohorts, and 2 hours for the last cohort (40 mg). CF102 showed good oral 
bioavailability and linear pharmacokinetics (PK) behavior. Single- and repeated-dose plasma 
concentrations of the drug were dose-proportionate. Decline of CF102 plasma concentration was 
at a moderate rate, with mean half-life estimates consistently ranging between ~11 and ~12 hours 
at all doses. 
Increases in Cmax and AUC values were dose-related up to a 20 mg dose. However, the mean 
Cmax and mean AUC(0-t) with the 40 mg dose were similar to those at the 20 mg dose level, 
suggesting exposure to CF102 might have reached a plateau between 20 mg and 40 mg. 
Pharmacokinetics parameters are summarized in Table 4-1 below. 
Table 4–1: 
Human Pharmacokinetic Parameters for CF102 
Mean (Std. Dev.) plasma CF102 pharmacokinetic parameters following single oral dose of CF102 in 
healthy male subjects (N=4 active per cohort) 
Dose 
(mg) 
Cmax 
(ng/mL) 
tmax
a 
(h) 
AUC(0-t)
 b 
(ng•h/mL) 
AUC(inf) 
(ng•h/mL) 
t1/2 
(h) 
CL/F 
(mL/h) 
1 
4.49±1.52 
4 (2-4) 
64.03±24.59 
68.91±24.45 
11.84±0.84 
16124±6302 
3  
21.91±8.52 
4 (2-4) 
330.7±112.1 
350.9±122 
11.47±1.49 
9571±4030 
10 
45.73±8.64 
4 (2-4) 
747.3±210.9 
796.2±251.1 
11.01±3.11 
13694±4949 
20 
104.9±15.8 
6 (6-6) 
1911±400.1 
2060±461.6 
11.84±2.39 
10128±2529 
40 
134.6±37.6 
2 (2-6) 
2052±894.7 
2239±1053 
12.25±2.05 
20809±8670 
a. 
Median (range) 
b. 
AUC(0-48h) 
 


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4.2.2 
Phase 1/2 Trial in Subjects with HCC (Study CF102-102HCC) 
An open-label trial was conducted in 19 subjects with advanced unresectable HCC to evaluate 
the safety and PK profile of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles 
(Stemmer, 2013). Evaluation of the antitumor effects and the utilization of A3AR as a biological 
predictive marker of response to CF102 were secondary objectives. 
CF102 demonstrated good oral bioavailability and linear PK behavior in subjects with Child-
Pugh A and B hepatic dysfunction. The best response by RECIST criteria was SD in 5/17 
subjects (29.4%). Median overall survival (OS) was 8.2 months for all subjects, 8.3 months for 
subjects with no prior sorafenib use, and 7.2 months for subjects with prior sorafenib and for 
Child-Pugh class A hepatic dysfunction subjects. Median OS in Child-Pugh class B hepatic 
dysfunction subjects was 9.5 months. 
These results are encouraging in light of the fact that 63% of the subject population had disease 
progression on sorafenib and that, for these subjects, CF102 treatment was second-line therapy. 
The most common adverse events (all causalities combined) were decreased appetite (52.6%); 
fatigue (42.1%); abdominal pain, constipation, and diarrhea (31.6% each); ascites and pyrexia 
(26.3% each); and nausea, asthenia, back pain, and pain in extremity (21.1% each). CF102-
related AEs included fatigue (26.3%), asthenia and decreased appetite (21.1% each), and pyrexia 
and constipation (15.8% each). Grade 3 drug-related AEs included: cerebral hemorrhage, 
headache, hyponatraemia, fatigue, asthenia, and back pain. One death (5.3%) due to cerebral 
hemorrhage was judged possibly related to CF102 by the Investigator. SAEs with fatal outcomes 
in 5 subjects were judged as not related to CF102. 
CF102 had no adverse effect on routine measures of liver function over a 6-month period in 12 
subjects treated for at least that duration. No dose-limiting toxicities were observed during the 
trial and the MTD was not reached. 
These findings corroborate clinical CF102 data published earlier that show a protective effect on 
normal liver tissue in an experimental model of liver inflammation (Cohen, 2011), and suggest 
that CF102 could be used in patients with cirrhosis and/or hepatic impairment. The highest dose 
tested of 25 mg BID, being well tolerated and showing a potentially favorable therapeutic index 
in subjects with HCC, was recommended for further clinical study. Please refer to the 
Investigational Brochure for additional information. 


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4.3 
Rationale for the Trial 
Liver cancer is the fifth most frequently diagnosed cancer in men worldwide, and is the second 
leading cause of cancer-related death in the world (Jemal, 2011). In women, it is the seventh 
most commonly diagnosed cancer and the sixth leading cause of cancer deaths. In the United 
States, liver cancer is the ninth leading cause of cancer death (Altekruse, 2009). The number of 
deaths per year in HCC is virtually identical to the incidence throughout the world (between 
250,000 and 1 million cases annually), underscoring the high case fatality rate of this aggressive 
disease (Jemal, 2011). Almost 80 percent of cases are due to underlying chronic hepatitis B and 
C virus infection (Perz, 2006). 
Treatments for HCC can be divided into those delivered with the intention to cure and those that 
are palliative and/or delay disease progression. Surgery and transplantation have the potential to 
cure the disease, but they are generally offered to only 30-40% of patients at early stages of the 
disease. There is no accepted standard treatment for advanced HCC. Palliative therapies include 
radiofrequency ablation, transarterial chemoembolization, and chemotherapy. None of these 
treatments have been shown to improve survival. 
The Child-Pugh classification system is used to assess the severity of liver disease, the prognosis, 
and the appropriate treatment. A Child- Pugh score of 5-6 is considered Class A (well-
compensated disease); a score of 7-9 is Class B (significant functional compromise); and a score 
of 10-15 is Class C (decompensated disease). 
Sorafenib (Nexavar®) is a new oral drug indicated for advanced HCC in patients with 
unresectable liver cancer. A randomized controlled trial comparing sorafenib to placebo in 
patients with advanced HCC and Child-Pugh Class A disease found that median survival and 
time to progression were nearly 3 months longer for patients treated with sorafenib compared to 
placebo (SHARP trial (Llovet, 2008). The median overall survival was 10.7 months in the 
sorafenib group and 7.9 months in the placebo group. There are no published, randomized 
controlled studies of the efficacy of sorafenib in patients with advanced HCC who have Child-
Pugh Class B (CPB) or Child-Pugh Class C cirrhosis. 
4.4 
Rationale for Amendment 5 
Amendment 5 implements the transition to open-label (OL) dosing for patients who are 
surviving and remain on drug at the time of analysis; and establishes the assessments and 
schedule of visits for the OL dosing aspect of the trial. This includes defining the OL eligibility 


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criteria; detailing the visit and assessment schedule; and specifying that the only patients still on 
treatment in this trial at the time of this amendment are in Romania. 
An ancillary change has been made to remove reference to the Modified Intent to Treat (MITT) 
Population, as such an analysis is deemed to be non-contributory to trial objectives. 
4.5 
Potential Risks and Benefits of Therapy 
4.5.1 
Risks 
Adverse events observed during CF102 therapy in the CF102-102HCC trial included the 
following: 
• 
Most common AEs (4 or more occurrences, all causalities combined): abdominal pain, 
ascites, diarrhea, edema, fatigue, fever, lack of appetite, pain, and weakness. 
• 
AEs considered possibly or probably related to CF102: pain in various bodily locations, 
fatigue, diarrhea, lack of appetite, weakness, and fever. 
• 
Of the 25 serious adverse events reported, ascites, cellulitis, cerebral hemorrhage, headache, 
hyponatremia, and leg thrombus were considered at least possibly related to CF102. 
For additional information, please refer to the Investigator Brochure. 
4.5.2 
Potential Benefits 
Previous experience has shown that the OS for Child-Pugh Class B patients with HCC is in the 
range of 3.5–5.5 months (Pinter, 2009; Pinter, 2011; Hollebecque, 2011). More importantly, data 
emerging from a number of recent trials have indicated that the median OS for patients with CPB 
and HCC who have failed treatment with sorafenib is generally no more than 2 months 
(Pinter, 2009; Wörns, 2009; Kim, 2011; Hollebecque, 2011; Abou-Alfa, 2011; Chiu, 2012; 
Køstner, 2013; Pressiani, 2013; Zugazagoitia, 2013). 
Considering that Child-Pugh Class B patients with HCC have few available treatment options, 
and that these patients when treated with sorafenib generally have poor outcomes with very 
limited OS due to underlying liver dysfunction, CF102 may offer a therapeutic option for this 
sub-population of patients. CF102 has the further advantage of lacking, to date, any evidence of 
hepatotoxicity, making it highly suitable for use in patients with CPB cirrhosis. 


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5.0 
TRIAL OBJECTIVES 
The primary objective of this trial is to: 
• 
Evaluate the efficacy of orally administered CF102 25 mg BID as compared to placebo, as 
determined by Overall Survival (OS), when used as second-line therapy in subjects with 
advanced hepatocellular carcinoma (HCC) and Child-Pugh Class B (CPB) cirrhosis. 
The secondary objectives of this trial are to: 
• 
Evaluate other indicators of efficacy of CF102 as compared to placebo, including time to 
progression (TTP), progression-free survival (PFS), objective response (OR) rate, and 
disease control (DC) rate in this population; 
• 
Explore the exposure-response relationships of oral CF102 using sparse PK sampling; 
• 
Characterize the safety profile of CF102 in subjects with advanced HCC and CPB cirrhosis; 
• 
Characterize the effects of CF102 on laboratory parameters associated with viral hepatitis, 
hepatic dysfunction, and cirrhosis; and 
• 
Explore the relationship between white blood cell (WBC) adenosine A3 receptor (A3AR) 
expression and clinical response. 
6.0 
INVESTIGATIONAL PLAN 
6.1 
Overall Trial Design and Plan Description 
This is a multicenter, randomized, double-blind, placebo-controlled trial in subjects with 
advanced HCC and CPB cirrhosis who did not tolerate prior sorafenib therapy or experienced 
disease progression on prior sorafenib therapy. 
The trial will evaluate the efficacy and safety of CF102 as compared to placebo. Subjects will be 
randomly assigned in a 2:1 ratio to treatment with oral doses of either CF102 25 mg capsules or 
matching placebo capsules administered twice daily (BID) for consecutive, 28-day cycles. 
Treatment will continue until the subject experiences unacceptable drug-related intolerability. 
Subjects who discontinue will be followed indefinitely for survival status. 
The primary efficacy endpoint will be OS, defined as the number of days from first dose to death 
due to any cause. Secondary endpoints to be evaluated are TTP, PFS, OR rate (consisting of 
Complete Response (CR) or Partial Response (PR) in subjects who enter with measurable 
disease by RECIST v1.1), and DC rate which includes subjects with OR as well as those with 
Stable Disease (SD). Survival status will be assessed continuously. Tumor status will be assessed 
at baseline and every 8 weeks thereafter (i.e., at the end of even-numbered cycles) by computed 
tomography (CT) scan or magnetic resonance imaging (MRI) according to RECIST v1.1 criteria 


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as modified by Santoro (2013) (Appendix A). Alpha-fetoprotein (AFP) levels will be assessed at 
baseline and every 4 weeks thereafter on Day 1 of each subsequent cycle. Laboratory parameters 
associated with hepatic dysfunction and cirrhosis, such as serum ALT, AST, bilirubin, and 
albumin levels; PT; and INR, will be assessed every cycle where applicable. Hepatitis B 
and/or C viral load measurements will be performed every odd-numbered cycle. White blood cell 
A3AR expression will be assessed at baseline and, unless waived by the Sponsor, every odd-
numbered cycle (at selected sites only). Sparse PK blood samples on Day 1 of Cycles 1 and 2 as 
well as trough samples collected on Days 8 and 15 of Cycle 1 will be used to generate a 
composite PK profile for subjects receiving CF102, and allow an exploratory analysis of 
exposure-response relationships for this trial. 
Subjects will be evaluated regularly for safety including changes in laboratory parameters 
including thyroid functions, vital signs, physical examination, ECOG PS, and ECG assessments 
compared to baseline findings. Subjects will return for a follow-up visit 28 days after completion 
of the last dose of study drug, and every attempt will be made to obtain subject survival data. 
Once the requisite number of events has occurred and the blind is opened for analysis of the trial 
results, any surviving subjects who remain on blinded drug will be offered the opportunity to 
continue dosing with open-label CF102 25 mg BID indefinitely, following the protocol-specified 
schedule of events (Table 1–2). 
6.2 
Discussion of Trial Design Including the Choice of Control Group 
The use of a placebo control group in this trial reflects clinical equipoise since subjects with 
advanced HCC and CPB cirrhosis who had failed one prior therapy for locally advanced or 
metastatic disease would otherwise have received best supportive care, because there are no 
proven or approved therapies for this patient population. Randomized, controlled trials are 
currently considered to be the clinical and scientific standard for Phase 2 trials of new drug 
treatments for HCC (Llovet, 2008; Thomas, 2010). 
Randomizing subjects in a 2:1 ratio ensures that 67% of subjects will receive the active agent, 
thus decreasing the number of subjects receiving placebo from that for a balanced randomization. 
Because overall survival is the primary endpoint of the trial, the potential impact of unintentional 
unblinding is considered to be minimal. 


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6.3 
Number of Subjects 
Approximately 78 subjects will be enrolled and randomized in a 2:1 ratio to receive treatment 
with either CF102 or matching placebo. 
6.4 
Duration of Trial 
The subject accrual period is estimated to be approximately 102 weeks (~24 months) in duration. 
Each treatment cycle will be 28 days of daily dosing. Study drug treatment may continue until 
the subject experiences unacceptable drug-related intolerability (Section 8.2). 
The post-accrual treatment period will continue until a total of 75 subjects have died. 
Once the requisite number of events has occurred and the blind is opened for analysis of the trial 
results, any surviving subjects who remain on blinded drug will be offered the opportunity to 
continue dosing with open-label CF102 25 mg BID indefinitely, following the protocol-specified 
schedule of events (Table 1–2). 
7.0 
SELECTION OF SUBJECTS 
7.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for the trial: 
1. 
Males and females at least 18 years of age. 
2. 
Diagnosis of HCC: 
□ 
For subjects without underlying cirrhosis at the time of diagnosis, diagnosis of HCC 
documented by cytology and/or histology. 
□ 
For subjects with underlying cirrhosis at the time of diagnosis, diagnosis of HCC 
established according to the American Association for the Study of Liver Diseases 
Practice Guideline algorithm (Appendix E). 
3. 
HCC is advanced, i.e., treatment-refractory or metastatic, and no standard therapies are 
expected to be curative. 
4. 
Receipt of prior sorafenib therapy for at least 3 weeks and withdrawal from treatment due 
either to intolerability or to radiographic evidence of disease progression. If treatment was 
withdrawn due to intolerability manifested as a Grade 3 or 4 event by National Cancer 
Institute Common Toxicity Criteria for Adverse Events (CTCAE v4.0), less than 3 weeks 
of continuous prior administration prior to withdrawal is acceptable (see also Exclusion 
Criterion #3). 
5. 
Prior sorafenib treatment was discontinued for at least 2 weeks prior to the Baseline Visit. 
6. 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2 (Appendix B). 


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7. 
Cirrhosis classified as Child-Pugh Class B (Appendix C). 
8. 
The following laboratory values must be documented ≤ 3 days prior to the first dose of 
study drug: 
□ 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
□ 
Platelet count ≥ 75 × 109/L 
□ 
Serum creatinine ≤ 2.0 mg/dL 
□ 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × the 
upper limit of normal (ULN) 
□ 
Total bilirubin ≤ 3.0 mg/dL 
□ 
Serum albumin ≥ 2.8 g/dL 
□ 
Prothrombin time (PT) no greater than 6 seconds longer than control. 
9. 
Life expectancy of ≥ 6 weeks. 
10. For women of childbearing potential, negative serum pregnancy test result. 
11. Provide written informed consent to participate. 
12. Willing to comply with scheduled visits, treatment plans, laboratory assessments, and other 
trial-related procedures. 
7.2 
Exclusion Criteria 
Subjects meeting any of the following criteria are ineligible for the trial: 
1. 
Receipt of no, or of > 1, prior systemic drug therapies for HCC. 
2. 
Receipt of systemic cancer therapy, immunomodulatory drug therapy, immunosuppressive 
therapy, or corticosteroids > 20 mg/day prednisone or equivalent within 14 days prior to the 
Baseline Visit or concurrently during the trial. 
3. 
Presence of an acute or chronic toxicity of prior chemotherapy that has not resolved to 
≤ Grade 1, as determined by CTCAE v 4.0. 
4. 
Locoregional treatment within 4 weeks prior to the Baseline Visit. 
5. 
Major surgery or radiation therapy within 4 weeks prior to the Baseline Visit. 
6. 
Use of any investigational agent within 4 weeks prior to the Baseline Visit. 
7. 
Child-Pugh Class A or C cirrhosis, or hepatic encephalopathy. 
8. 
Occurrence of esophageal or other gastrointestinal hemorrhage requiring transfusion within 
4 weeks prior to the Baseline Visit. 
9. 
Uncontrolled or clinically unstable thyroid disease, per judgment of the Principal 
Investigator. 
10. Active bacterial, viral, or fungal infection requiring systemic therapy, or operative or 
radiological intervention. 


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11. Known human immunodeficiency virus- or acquired immunodeficiency syndrome-related 
illness. 
12. Liver transplant. 
13. Active malignancy other than HCC. 
14. Uncontrolled arterial hypertension or congestive heart failure (New York Heart Association 
Classification 3 or 4) (Appendix B). 
15. Angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass 
graft surgery, transient ischemic attack, or pulmonary embolism within 3 months prior to 
initiation of study drug. 
16. History of or ongoing cardiac dysrhythmias requiring treatment, atrial fibrillation of any 
grade, or persistent prolongation of the QTc (Fridericia) interval to > 450 msec for males or 
> 470 msec for females. 
17. Pregnant or lactating female. 
18. Women of childbearing potential, unless they agree to use dual contraceptive methods 
which, in the Investigator’s opinion, are effective and adequate for the subject’s 
circumstances while on study drug. 
19. Men who partner with a woman of childbearing potential, unless they agree to use effective, 
dual contraceptive methods (i.e., a condom, with female partner using oral, injectable, or 
barrier method) while on study drug and for 3 months afterward. 
20. Any severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality 
that may increase the risk associated with trial participation or study drug administration; 
may interfere with the informed consent process and/or with compliance with the 
requirements of the trial; or may interfere with the interpretation of trial results and, in the 
Investigator’s opinion, would make the subject inappropriate for entry into this trial. 
7.3 
Randomization and Blinding 
On Day 1, each subject will be randomly assigned in a 2:1 ratio to receive either CF102 25 mg 
BID or placebo BID. A randomization schedule will be prepared for treatment group assignment 
of each subject. The subject’s randomization number will be unique. This number is not the same 
as the subject identification (ID) number which is assigned at the time of informed consent. The 
subject ID number identifies the subject and consists of the site number plus subject number for 
that site. The randomization number identifies the treatment; the randomization schedule 
provides the correspondence between the subject ID number and the randomization number. 
The trial will be double-blind, meaning the subject and Investigator/staff will not have access to 
or knowledge of the subject’s treatment assignment. 


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Additional details regarding randomization and procedures for unblinding the treatment 
assignment for individual subjects will be provided in the Pharmacy Manual or other separate 
documentation. 
7.4 
Discontinuation from Dosing 
Discontinuation from dosing means that upon the subject’s decision to terminate dosing early, 
the End of Study visit is to be performed and indefinite monthly survival follow up will be 
performed. 
Subjects should be discontinued from dosing for the following reasons: 
• 
Grade 3 toxicity considered by the Investigator to be at least “possibly” drug-related that 
does not resolve to Grade ≤ 1 within 7 days following interruption of treatment. 
• 
Need for > 1 dose reduction. 
• 
Grade 4 toxicity considered by the Investigator to be at least “possibly” drug-related. 
• 
Treatment interruption or delay for more than 14 days after the next scheduled dose due to 
an event unrelated to toxicity (e.g., intercurrent illness, scheduled surgery, etc). 
• 
Subject withdrawal of consent for trial participation at any time, for any reason, and without 
prejudice. 
• 
Withdrawal of a subject by the Investigator, at his/her discretion, for any reason that the 
Investigator believes continuation of study drug therapy would not be in the subject’s best 
interest. The reason for the subject’s discontinuation must be recorded on the case report 
form (CRF). 
• 
An intercurrent illness which, in the Investigator’s opinion, would prevent completion of 
trial-related evaluations. 
• 
Pregnancy. 
• 
Subject noncompliance with trial or follow-up procedures. 
• 
Termination of the trial by the Sponsor. 
If a subject is withdrawn from treatment, the Investigator will make every effort to complete all 
final evaluations and laboratory tests required by the protocol. The reason(s) for discontinuation 
of dosing must be clearly documented on the CRF. Subjects who discontinue will be followed 
indefinitely for survival status. 


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7.5 
Withdrawal from the Trial 
A subject will be considered to be withdrawn from the trial for the following reasons: 
• 
Withdrawal of consent (in which every effort will be made to follow the subject for survival 
information). 
• 
Lost to Follow-up (subject does not return for trial visits and contact cannot be 
reestablished). 
• 
Termination of the trial by the Sponsor. 
7.6 
Replacement of Subjects 
No replacement of subjects is planned in this trial. 
7.7 
Eligibility Criteria for Open Label 
• 
The subject signed the ICF for the Open Label treatment. 
• 
The subject received double blind treatment with CF102/placebo and is still taking the 
investigational medication when Amendment 5 is approved. 
8.0 
TREATMENTS 
Study drug is to be administered only to subjects who have provided informed consent and have 
met the criteria outlined in 7.1 Inclusion Criteria and 7.2 Exclusion Criteria. 
Open-label CF102 is to be administrated only to subjects who have provided informed consent 
for the open label treatment and met the criteria outlined in 7.7 Eligibility Criteria for Open 
Label. 
8.1 
Treatments Administered 
CF102 or matching placebo will be administered in continuous 28-day cycles beginning on Day 
1 of Cycle 1. 
During OL the CF102 will be administrated in continuous 28-days cycles beginning on Day 1 of 
Cycle 1 of OL period. 
Subjects will self-administer CF102 or placebo twice daily (BID) beginning on Day 1 of the trial. 
Study drug should be taken on an empty stomach (1 hour before or 2 hours after meals) at 
approximately the same times each day of the 28-day cycle. On days of a scheduled clinic visit, 
the dose of CF102 or placebo should be taken at the clinic after visit procedures have been 
completed. Missed or vomited doses will not be “made up.” 


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8.2 
Dose Modification 
Any safety-related modification of study drug dosing (i.e., dose reduction or interruption of 
scheduled dosing) and the reason for such action must be clearly noted on the Adverse Events 
page of the CRF, and the Medical Monitor informed. 
In the case of any Grade 3 toxicity by CTCAE v4.0 judged by the Principal Investigator to be at 
least “possibly” drug-related, the dose of study drug will be interrupted for up to 7 days. If 
toxicity does not resolve to Grade ≤ 1 within 7 days, the subject will be discontinued from 
treatment. If toxicity does resolve to Grade ≤ 1 within 7 days, dosing will be resumed at the 
decreased dose of 1 capsule per day. 
In the case of any Grade 4 toxicity judged by the Principal Investigator to be at least “possibly” 
drug-related, the dose of study drug will be withdrawn permanently. 
Only 1 dose reduction will be allowed. If a Grade 3 or 4 toxicity judged by the Principal 
Investigator to be at least “possibly” drug-related occurs upon rechallenge at the reduced dose, 
study drug dosing will be withdrawn permanently. 
All changes in dosing will be recorded on the CRF. 
8.3 
Study Drug Identification 
All study drug product is intended for oral administration. CF102 is formulated as opaque, white, 
size 3, Coni-Snap hard gelatin capsules containing 25 mg of CF102 active pharmaceutical 
ingredient. Matching placebo is formulated as opaque, white, size 3, Coni-Snap hard gelatin 
capsules containing inactive ingredients (microcrystalline cellulose, maltodextrin, sodium lauryl 
sulfate, and imperial talc 500). 
CF102 and placebo capsules are stable under long-term storage conditions (25°C/60% RH). 
Excursions to elevated temperatures (40°C/75% RH) are permitted. 
8.4 
Packaging and Labeling 
CF102 and matching placebo capsules are packaged in 75cc white, high-density polyethylene 
(HDPE) wide-mouth oblong bottles capped with 33 mm white, HDPE ribbed caps (child 
resistant) with a heat seal inner foil liner. 
Study drug supplies will be shipped to the investigational site and /or investigational site 
pharmacy by CSM (Fargo, ND). The pharmacist will prepare individual bottles of study drug to 


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dispense to subjects based on their randomized treatment assignment. The labels on the subject 
bottles will include the following: 
• 
Number and strength of capsules; route of administration 
• 
Directions for use 
• 
Storage conditions 
• 
Product ID code 
• 
Protocol number 
• 
Sponsor’s name 
• 
The statement: “Caution: New drug-limited by Federal Law to Investigational Use. Keep 
out of reach of children.” 
• 
Subject randomization number 
8.5 
Study Drug Handling and Accountability 
The Investigator (or designee, i.e., investigational site pharmacist) at the site will be responsible 
for handling study drug and maintaining required documentation. The Investigator must maintain 
complete and current inventory and dispensing records supplied by the Sponsor. 
The Investigator (or designee) will: 
• 
Ensure study drug supplies are stored at stable room temperature (20-25°C) in an 
appropriately controlled limited-access room in a secure location. 
• 
Dispense the appropriate study drug according to the subject’s randomized treatment 
assignment. 
• 
Record pertinent information regarding the dose of study drug dispensed (e.g., subject ID 
number, date, number of doses/bottles dispensed, etc.) on the Drug Dispensing Log, or 
other appropriate inventory form. This inventory will be maintained throughout the trial and 
will be reviewed periodically by a Sponsor representative. 
• 
Inform subjects that at each clinic visit and at the end of their participation in the trial, all 
partially used and empty pill bottles must be returned to the Investigator so that a final 
inventory may be conducted. Once returned to the Investigator, capsules from partially-
used bottles will not be re-dispensed to another subject. 
8.6 
Treatment Compliance 
Bottles of study drug dispensed to subjects at the start of each treatment cycle will contain a 
sufficient supply of CF102 or matching placebo for 28 days of continuous dosing (1 cycle). 
Treatment compliance will be monitored by the investigative site staff at each clinic visit. 


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Bottles of study drug dispensed to subjects at the start of each treatment OL cycle will contain a 
sufficient supply of CF102 for 28 days of continuous dosing (1 cycle). Treatment compliance 
will be monitored by the investigative site staff at each clinic visit. 
The Investigator will instruct subjects to bring all partially used and empty pill bottles to each 
clinic visit. Any dosing error will be reported to the Investigator and Sponsor’s monitor. 
8.7 
Study Drug Disposal 
Throughout the trial, the Investigator will maintain a careful inventory of all partially used and 
empty bottles of study drug. 
Periodically throughout and at the conclusion of the trial, an inventory of unused bottles of study 
drug will be conducted by a Sponsor representative. At the completion of the trial, all partially 
used as well as all unused study drug materials must be returned to the Sponsor or destroyed on 
site, with appropriate documentation. 
At the termination of the trial, a final drug accountability review and reconciliation must be 
completed and any discrepancies must be investigated and their resolution documented. 
8.8 
Concomitant Medications and Supportive Care 
All prior anti-neoplastic medications, medications taken within 1 month prior to the Baseline 
Visit, and concomitant medications will be collected from the time the subject signs the consent 
form and throughout the trial, including the Follow-Up Visit, and recorded on the appropriate 
Case Report Form. Medications/treatments that affect trial eligibility are listed in the Inclusion 
and Exclusion criteria in Sections 7.1 and 7.2. 
During the trial, all medications considered necessary for the subject’s welfare and that are not 
expected to interfere with the evaluation of the study drug may be administered at the 
Investigator’s discretion. If site personnel have any questions regarding the suitability of a 
particular concomitant medication, the Medical Monitor should be contacted. 
There is no requirement for premedication with CF102. Any medications administered for either 
prophylaxis or treatment of symptoms associated with study drug should be documented on the 
Concomitant Medication page of the CRF. 
The following are prohibited from concomitant administration with CF102: 
1. 
Systemic cancer therapy, immunomodulatory drug therapy, immunosuppressive therapy, or 
radiotherapy 


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2. 
Corticosteroids > 20 mg/day prednisone or equivalent 
3. 
Hematopoietic growth factors may not be given prophylactically but may be administered 
to treat toxicity. 
9.0 
EFFICACY AND SAFETY VARIABLES ASSESSED 
9.1 
Trial Visits 
All subjects will be assessed by scheduled clinical, laboratory, and other diagnostic assessments 
throughout the trial. See the flow chart (Table 1–1 and Table 1–2) for the timing of trial 
procedures and assessments to be performed at each clinic visit. 
Pre-Study (i.e., Screening) assessments are to be performed within 28 days prior to first study 
drug dose, unless otherwise specified. 
The first day of study drug dosing will be considered Day 1 (Baseline) of the trial. 
Clinic Visits will take place within ± 2 working days of the scheduled time unless a waiver is 
approved by the Sponsor. Trial assessments will be performed prior to administration of the 
study drug dose for that day. 
If significant changes from baseline are noted during the trial, additional unscheduled clinic 
visits may be performed in order to determine the relevance of findings and/or the duration of 
events. 
End of Dosing assessments are to be performed within 2 working days after the last dose of 
study drug. 
A Follow-Up visit is to be scheduled 28 ± 3 days after the End of Dosing visit to perform all 
final safety assessments and collect information on any adverse events. 
The subjects who are still on blinded treatment when the Amendment 5 is approved will be 
switched to open label treatment at their next scheduled visit. During this visit, the Cycle 1 Day 1 
for OL procedures will be performed (Table 1-2). In OL period, Clinic Visits will take place 
within ± 2 working days of the scheduled day unless a waiver is approved by the Sponsor. Trial 
assessments will be performed prior to administration of the study drug dose for that day. 
The first day of open label study drug dosing will be considered Day 1 (OL) of the trial. 


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9.2 
Trial Assessments 
9.2.1 
Informed Consent 
All subjects must take part in the informed consent process. Adequate time must be allowed for 
the subject to ask questions and make a voluntary decision. No protocol specific procedures, 
including Pre-Study screening procedures, are to be performed until the subject has signed and 
dated an IRB/EC-approved informed consent form (ICF). The ICF can be signed outside of the 
Pre-Study period; however, no protocol-related procedures can be performed until the consent 
has been signed. Documentation of the informed consent process must be noted in the subject’s 
source documents. The subject ID number will be assigned after the ICF is signed. 
The subjects will receive CF102 in open label portion of the trial only after the subject signs and 
dates the IRB/EC-approved informed consent form (ICF) for the OL. 
9.2.2 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be collected at the Pre-Study (Screening) Visit. 
Baseline characteristics consist of a complete medical history and detailed disease history. 
Medical history includes prior and ongoing medical diagnoses and conditions, surgical 
procedures not related to the primary diagnosis, and medications taken within the previous 30 
days. 
Disease history is a history of the primary diagnosis and should include the date of initial HCC 
diagnosis and staging; date of most recent relapse and/or re-staging; histologic or cytologic 
diagnosis; prior treatments (e.g., chemotherapy, surgery, radiation), dates of treatments, numbers 
of cycles, and best response to such treatments; duration of prior sorafenib therapy; reason(s) for 
discontinuation of sorafenib, and if applicable, nature of intolerability to sorafenib; current signs 
and symptoms related to the primary diagnosis; and location and measurement of target and non-
target sites of disease. 
9.2.3 
Concomitant Medications 
All prior and concomitant medications will be collected from the time of the Pre-Study Visit 
throughout the trial, including the OL period and OL Follow-Up Visit 28 days after the last dose 
of study drug. The information will include: the name of the drug (including generic when 
known), the indication for which it was used, total daily dosage, and duration of treatment. Any 
diagnostic, therapeutic, or surgical procedures performed during the trial (e.g., blood transfusion) 
should be recorded on this form, including the date, indication, description, and findings, if any. 


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9.2.4 
Adverse Event Assessments 
Information regarding the occurrence of adverse events will be collected from the Cycle 1 Day 1 
visit (i.e., the Baseline Visit) throughout the trial, including the OL period and OL Follow-Up 
Visit 28 days after the last dose of study drug. If AEs related to study drug are ongoing at the OL 
Follow-Up Visit, safety data will be collected until the adverse event resolves or stabilizes. 
9.2.5 
ECOG Performance Status 
Performance status will be assessed using ECOG PS criteria (Appendix B). 
9.2.6 
Vital Signs 
Vital signs will be measured after the subject has been seated for 5 minutes. Vital signs will 
include blood pressure (mm Hg), heart rate (beats per minute), respiration rate (breaths per 
minute), and temperature (degrees Celsius). 
9.2.7 
Physical Examination (PE) 
A complete physical examination (PE) will be performed by the Investigator or Sub-Investigator 
at the Pre-Study, Day 1 (the Baseline Visit if not performed within 3 days prior), and End of 
Study/End of Dosing (EOS) visits/OL End of Study/OL End of Dosing (EOS) visits. The 
complete PE will include a thorough review of all body systems as well as measurement of 
weight (kg) and height (cm). 
At all other visits, a symptom-directed PE, including weight (kg), will be performed covering 
targeted body systems. 
9.2.8 
Laboratory Assessments 
Laboratory tests (hematology, clinical chemistry, coagulation, and urinalysis) will be performed 
at the Pre-Study Visit; Days 1 (i.e., the Baseline Visit if not performed within 3 days prior), 8, 
and 15 of Cycle 1; Days 1 and 15 of subsequent cycles; EOS; and Follow-up/ Days 1, 8, and 15 
of Cycle 1 OL; Days 1 and 15 of subsequent OL cycles; OL EOS; and OL Follow-up. Thyroid 
function tests (T3, T4, thyroid stimulating hormone [TSH]) will be performed at Pre-Study; 
Baseline; Day 1 of subsequent cycles; EOS; and Follow-up/ Baseline OL; Day 1 of subsequent 
OL cycles; OL EOS; and OL Follow-up. A serum β-hCG pregnancy test should be performed 
within 3 days prior to first study drug dose for all females of childbearing potential (defined as 
women ≤ 50 years of age or history of amenorrhea for ≤ 12 months prior to entering the trial). 
Where applicable, hepatitis B and/or C viral load measurements will be performed (for subjects 
with measurable viral load at baseline). 


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A complete list of laboratory tests is provided in Appendix D. 
9.2.9 
WBC A3AR Expression 
At selected sites, a blood sample will be obtained at the Cycle 1 Day 1 (Baseline) visit, prior to 
dosing. 2.5 mL of blood are to be collected. The complete procedure is detailed in the laboratory 
manual provided by the central laboratory. 
Sampling will be repeated at the beginning of every odd-numbered cycle, unless waived by the 
Sponsor. 
9.2.10 
Electrocardiogram (ECG) 
A 12-lead ECG will be performed at the following times after the subject has been supine for 5 
minutes: Pre-Study; pre-dose at all visits/pre-dose at all OL visits; Cycle 1 Days 1 and 8 at 2, 4, 
and 6h (± 10 min) post-dose/OL Cycle 1 Days 1 and 8 at 2, 4, and 6h (± 10 min) post-dose; and 
at Follow-up/OL Follow-up. 
9.2.11 
Tumor Assessment 
At the Pre-Study visit, an assessment of disease status will be determined using RECIST V1.1 
criteria as modified by Santoro (2013) (Appendix A). For the purposes of trial eligibility, a scan 
obtained within 14 days prior to the Pre-Study visit may be used. The location and dimensions of 
target lesions will be documented on the CRF. 
9.2.12 
Response Assessment 
Response assessments will be performed and documented throughout the trial using RECIST 
v1.1 (Appendix A). 
The same method/technique for assessing response, either CT scan or MRI, should be used for 
any individual subject throughout the trial. If progressive disease (PD) is documented at any 
time, the patient will not be discontinued from the trial. Further imaging or target lesion 
measurements will not be required and all other trial visits and procedures will continue. 
Diagnostic studies documenting disease response must be available for review by the Sponsor, if 
requested. 
In the event of an objective response, the duration of the response will be determined from the 
day the initial response is observed (using the Pre-Study Visit images for comparison) to the day 
that progression is observed. Duration of stable disease will also be assessed (see Appendix A). 


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9.2.13 
Pharmacokinetics Sampling 
Blood samples will be collected from all subjects enrolled at sites with the requisite technical 
capabilities during Cycle 1 on Days 1, 8, and 15 and on Day 1 of Cycle 2 to determine plasma 
concentrations of CF102. The sampling time points are shown in Table 10–1. Pharmacokinetic 
(PK) analyses will include area under the curve (AUC0-12h), maximum plasma concentration 
(Cmax), trough plasma concentration (Cmin), time to maximum plasma concentration (Tmax) 
following the morning dose on Day 1 of Cycles 1 and 2 and Cmin on Days 8 and 15 of Cycle 1. 
9.3 
Timing of Assessments 
9.3.1 
Pre-Study (Screening) Visit (-28 Days) 
The following assessments are to be performed Pre-Study within 28 days prior to the first dose of 
study drug, unless otherwise specified. 
• 
Medical history 
• 
Complete physical examination  
• 
Inclusion/exclusion criteria 
• 
Informed consent 
• 
Vital signs (Section 9.2.6) 
• 
Laboratory assessments including thyroid functions (Section 9.2.8) 
• 
Serum β-hCG pregnancy test (Section 9.2.8). If performed ≤ 3 days prior to first dose of 
study drug, need not be repeated at the Baseline Visit (Section 9.3.2) 
• 
ECG (Section 9.2.10) 
• 
ECOG PS (Section 9.2.5) 
• 
Hepatitis B and/or C virus serology 
• 
Tumor imaging for RECIST (need not be repeated if performed within the previous 21 
days) 
• 
Concomitant medications (taken within the previous 30 days) 
9.3.2 
Cycle 1 Day 1 (Baseline) Visit 
The following assessments will be performed at the Cycle 1 Day 1 (Baseline) Visit prior to the 
first dose of study drug, and at other times as specified: 
• 
Complete physical examination unless performed ≤ 3 days prior to first dose 
• 
Vital signs (Section 9.2.6) 
• 
Laboratory assessments including thyroid functions (Section 9.2.8) unless performed ≤ 3 
days prior  
• 
Serum β-hCG pregnancy test (Section 9.2.8) unless performed ≤ 3 days prior 


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• 
ECG pre-dose and at 2, 4, and 6h (± 10 min) post-dose (Section 9.2.10) 
• 
ECOG PS (Section 9.2.5) unless performed ≤ 3 days prior 
• 
AFP 
• 
WBC A3AR sample (selected sites only) (Section 9.2.9) 
• 
PK sampling (selected sites; Table 10–1) 
• 
Hepatitis B and/or C viral load (if seropositive) 
• 
Concomitant medications 
• 
Administer the first dose of study drug and record the time of administration 
• 
Adverse events (post-dosing) 
• 
Dispense the balance of Cycle 1 study drug supplies 
• 
Instruct the subject regarding treatment compliance, and (at selected sites) not to take the 
dose prior to PK sampling on the morning of Days 8 and 15 
9.3.3 
Cycle 1 Day 8 and Day 15 Visits (± 2 days) 
The following assessments will be performed prior to the daily dose of study drug: 
• 
Physical examination (symptom-directed) 
• 
Vital signs (Section 9.2.6) 
• 
Laboratory assessments (Section 9.2.8) 
• 
ECG pre-dose (Days 8 and 15); and at 2, 4, and 6h (± 10 min) post-dose (Day 8 only) 
(Section 9.2.10) 
• 
Trough PK sample pre-AM dose) 
• 
Concomitant medications 
• 
Adverse events 
• 
Review treatment compliance 
• 
Instruct the subject not to take the dose prior to PK sampling on the morning of Cycle 2 
Day 1 (selected sites) 
9.3.4 
Subsequent Cycles Day 1 Visit (± 2 days) 
The following assessments will be performed prior to the daily dose of study drug: 
• 
Physical examination (symptom-directed) 
• 
Vital signs (Section 9.2.6) 
• 
Laboratory assessments including thyroid functions (Section 9.2.8) 
• 
Serum β-hCG pregnancy test (Section 9.2.8) if indicated 
• 
ECG pre-dose (Section 9.2.10) 
• 
ECOG PS (Section 9.2.5) 


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• 
AFP 
• 
WBC A3AR sample (selected sites only; beginning of odd-numbered cycles only, unless 
waived by the Sponsor) (Section 9.2.9) 
• 
PK sampling (Table 10–1) (Note: Day 1 of Cycle 2 only; selected sites) 
• 
Tumor imaging for RECIST (at end of Cycle 2 and end of subsequent even-numbered 
cycles, with a time window of up to 7 days prior or 1 day after; if 1 day after, scan is to be 
done prior to the AM dose) (Appendix A) 
• 
Hepatitis B and/or C viral load (for subjects with measurable viral load at the Baseline 
Visit) (beginning of odd-numbered cycles only) 
• 
Concomitant medications 
• 
Adverse events 
• 
Collect used study drug supplies 
• 
Dispense study drug supplies 
• 
Review treatment compliance 
9.3.5 
Subsequent Cycles Day 15 Visit (± 2 days) 
The following assessments will be performed prior to the daily dose of study drug: 
• 
Physical examination (symptom-directed) 
• 
Vital signs (Section 9.2.6) 
• 
Laboratory assessments (Section 9.2.8) 
• 
ECG pre-dose (Section 9.2.10) 
• 
Concomitant medications 
• 
Adverse events 
• 
Review treatment compliance 
9.3.6 
End of Study/End of Dosing (EOS) Visit (within 2 days of last dose) 
• 
Physical examination (complete examination) 
• 
Vital signs (Section 9.2.6) 
• 
Laboratory assessments including thyroid functions (Section 9.2.8) 
• 
Serum β-hCG pregnancy test (Section 9.2.8) if indicated 
• 
ECG (Section 9.2.10) 
• 
ECOG PS (Section 9.2.5) 
• 
AFP 
• 
Hepatitis B and/or C viral load (for subjects with measurable viral load at the Baseline Visit) 
• 
Tumor imaging for RECIST (Appendix A) 
• 
Concomitant medications 


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• 
Adverse events 
• 
Review treatment compliance and collect all used study drug supplies 
9.3.7 
Follow-Up Visit (28 ± 3 days Post End of Dosing) 
• 
Physical examination (symptom-directed) 
• 
Vital signs (Section 9.2.6) 
• 
Laboratory assessments including thyroid functions (Section 9.2.8) 
• 
Serum β-hCG pregnancy test (Section 9.2.8) if indicated 
• 
ECG (Section 9.2.10) 
• 
AFP 
• 
Hepatitis B and/or C viral load (for subjects with measurable viral load at the Baseline Visit) 
• 
Concomitant medications 
• 
Adverse events 
9.3.8 
Cycle 1 Day 1 OL Visit 
The following assessments will be performed at the Cycle 1 Day 1 (OL) Visit prior to the first 
dose of study drug in OL, and at other times as specified: 
• 
Complete physical examination 
• 
Vital signs (Section 9.2.6) 
• 
Laboratory assessments including thyroid functions (Section 9.2.8) 
• 
Serum β-hCG pregnancy test (Section 9.2.8) 
• 
ECG pre-dose and at 2, 4, and 6h (± 10 min) post-dose (Section 9.2.10) 
• 
ECOG PS (Section 9.2.5) 
• 
AFP 
• 
WBC A3AR sample (selected sites only) (Section 9.2.9) 
• 
Hepatitis B and/or C viral load (if seropositive) 
• 
Concomitant medications 
• 
Administer the first dose of study drug in OL and record the time of administration  
• 
Adverse events (post-dosing) 
• 
Dispense the balance of Cycle 1 OL study drug supplies 
9.3.9 
Cycle 1 Day 8 OL and Day 15 OL Visits (± 2 days) 
The following assessments will be performed prior to the daily dose of study drug: 
• 
Physical examination (symptom-directed) 
• 
Vital signs (Section 9.2.6) 


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• 
Laboratory assessments (Section 9.2.8) 
• 
ECG pre-dose (Days 8 OL and 15 OL); and at 2, 4, and 6h (± 10 min) post-dose (Day 8 OL 
only) (Section 9.2.10) 
• 
Concomitant medications 
• 
Adverse events 
• 
Review treatment compliance 
9.3.10 
Subsequent Cycles Day 1 OL Visit (± 2 days) 
The following assessments will be performed prior to the daily dose of study drug: 
• 
Physical examination (symptom-directed) 
• 
Vital signs (Section 9.2.6) 
• 
Laboratory assessments including thyroid functions (Section 9.2.8) 
• 
Serum β-hCG pregnancy test (Section 9.2.8) if indicated 
• 
ECG pre-dose (Section 9.2.10) 
• 
ECOG PS (Section 9.2.5) 
• 
AFP 
• 
WBC A3AR sample (selected sites only; beginning of odd-numbered cycles only, unless 
waived by the Sponsor) (Section 9.2.9) 
• 
Tumor imaging for RECIST (at end of Cycle 2 and end of subsequent even-numbered 
cycles, with a time window of up to 7 days prior or 1 day after; if 1 day after, scan is to be 
done prior to the AM dose) (Appendix A) 
• 
Hepatitis B and/or C viral load (for subjects with measurable viral load at the Baseline 
Visit) (beginning of OL odd-numbered cycles only) 
• 
Concomitant medications 
• 
Adverse events 
• 
Collect used study drug supplies 
• 
Dispense study drug supplies 
• 
Review treatment compliance 
9.3.11 
Subsequent Cycles Day 15 OL Visit (± 2 days) 
The following assessments will be performed prior to the daily dose of study drug: 
• 
Physical examination (symptom-directed) 
• 
Vital signs (Section 9.2.6) 
• 
Laboratory assessments (Section 9.2.8) 
• 
ECG pre-dose (Section 9.2.10) 
• 
Concomitant medications 


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• 
Adverse events 
• 
Review treatment compliance 
9.3.12 
End of Study/End of Dosing (EOS) OL Visit (within 2 days of last dose) 
• 
Physical examination (complete examination) 
• 
Vital signs (Section 9.2.6) 
• 
Laboratory assessments including thyroid functions (Section 9.2.8) 
• 
Serum β-hCG pregnancy test (Section 9.2.8) if indicated 
• 
ECG (Section 9.2.10) 
• 
ECOG PS (Section 9.2.5) 
• 
AFP 
• 
Hepatitis B and/or C viral load (for subjects with measurable viral load at the Baseline Visit) 
• 
Tumor imaging for RECIST (Appendix A) 
• 
Concomitant medications 
• 
Adverse events 
• 
Review treatment compliance and collect all unused study drug supplies 
9.3.13 
Follow-Up OL Visit (28 ± 3 days Post OL End of Dosing) 
• 
Physical examination (symptom-directed) 
• 
Vital signs (Section 9.2.6) 
• 
Laboratory assessments including thyroid functions (Section 9.2.8) 
• 
Serum β-hCG pregnancy test (Section 9.2.8) if indicated 
• 
ECG (Section 9.2.10) 
• 
AFP 
• 
Hepatitis B and/or C viral load (for subjects with measurable viral load at the Baseline Visit) 
• 
Concomitant medications 
• 
Adverse events 
10.0 
EFFICACY AND PHARMACOKINETICS ASSESSMENTS 
10.1 
Response Assessments 
Data on primary disease, response, and the duration of any OR or SD, as well as the TTP, PFS, 
and OS will be collected for all subjects. Subjects will undergo disease assessment at Pre-Study 
(within 28 days prior to first dose of study drug), at the end of Cycle 2, and at the end of even-
numbered cycles thereafter. Response will be determined by RECIST version 1.1 as modified by 
Santoro (2013) (Appendix A). 


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Disease parameters to be assessed: 
• 
Diagnostic imaging/measurement of target lesions 
• 
Response assessment 
10.1.1 
Disease Classification 
Details of the primary diagnosis should be documented at the Pre-Study Visit. The histological/ 
cytological type (if known) and stage of disease should be noted on the CRF. 
10.1.2 
Diagnostic Imaging/Measurement of Target Lesions 
Subjects should be followed with the same imaging procedure (CT scan or MRI) throughout this 
trial. If PD is documented at any time, no further imaging or lesion measurements will be 
required. Diagnostic studies documenting response must be available for Sponsor review. 
10.1.3 
Response Assessment 
Response will be assessed as detailed in Appendix A. Efficacy will be assessed for the Intent-to-
Treat (ITT) Population (Section 12.3.2). 
10.2 
Time to Event 
The time to event assessments include OS, TTP, and PFS. Overall Survival (OS) is the number 
of days from Day 1 of Cycle 1 to the day of death+1, where a death can be due to any cause. 
Subjects who discontinue will be followed indefinitely to obtain survival status. Time to 
Progression (TTP) is the number of days from Day 1 of Cycle 1 to the day of PD+1. Progression-
Free Survival is the number of days from Day 1 of Cycle 1 to the day of death or PD+1. 
10.3 
Laboratory Assessments for Exploratory Efficacy 
Certain laboratory parameters associated with hepatic dysfunction and cirrhosis will be 
examined, as will WBC A3AR expression. 
10.3.1 
Liver Chemistry Tests 
Bilirubin (direct and total), ALT, AST, and albumin will be performed along with other 
laboratory tests assessed for safety at Pre-Study Visit; Days 1 (i.e., the Baseline Visit if not 
performed within 3 days prior), 8, and 15 of Cycle 1; Days 1 and 15 of subsequent cycles; EOS; 
and Follow-up/Days 1, 8, and 15 of OL Cycle 1; Days 1 and 15 of subsequent OL cycles; OL 
EOS; and OL Follow-up. 


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10.3.2 
INR 
INR will be assessed along with other laboratory tests assessed for safety at the Pre-Study Visit; 
Days 1 (i.e., the Baseline Visit if not performed within 3 days prior), 8, and 15 of Cycle 1; Days 
1 and 15 of subsequent cycles; EOS; and Follow-up/ Days 1, 8, and 15 of OL Cycle 1; Days 1 
and 15 of subsequent OL cycles; OL EOS; and OL Follow-up. 
10.3.3 
Viral Load 
For subjects with measurable viral load at the Baseline Visit, hepatitis B and/or C viral load will 
be measured on Day 1 of odd-numbered cycles/ Day 1 of OL odd-numbered cycles only. 
10.4 
Pharmacokinetics Assessment 
All subjects enrolled at sites with the requisite technical capabilities will have approximately 8 
whole blood samples collected during Cycle 1 and 2 for analysis of plasma concentrations of 
CF102. Approximately 4 mL of blood will be collected from subjects at each time point (i.e., a 
total of approximately 32 mL). 
The timing of PK sampling is shown in Table 10-1. Sparse PK samples will be collected 
following the morning dose of CF102 on Cycle 1 Day 1 and Cycle 2 Day 1. In addition, a trough 
sample will be collected pre-AM dose on Cycle 1 Days 8 and 15. If PK samples are to be drawn 
at a scheduled safety evaluation visit, the study drug should be held until after the pre-dose PK 
sample has been drawn and safety assessments have been performed. 
Table 10–1: Timing of PK Samples 
Timing Relative to Time of AM Dose (T) 
Cycle 1 
Cycle 2 
Day 1 
Day 8 
Day 15 
Day 1 
Pre-dose (AM dose) 
X 
X 
X 
X 
Post-dose 1, 2, 3, 4, 6, 8, and 12h (prior to the 
evening dose) a 
X 
 
 
X 
a. 
On Day 1 of Cycles 1 and 2, after the morning dose, PK blood samples will be collected at ANY TWO of the specified time 
points (1, 2, 3, 4, 6, 8, and 12h [prior to evening dose]) 
 
Plasma CF102 concentration will be determined using a validated LC-MS/MS method by a 
Sponsor-designated laboratory. 
10.4.1 
Sample Storage 
Plasma samples will be placed in a storage freezer at -70°C (± 12°C) or on dry ice within 120 
minutes of the blood collection. Samples should be placed in a -70°C (± 12°C) freezer until they 


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are shipped to the bioanalytical laboratory. With prior approval from the Sponsor, sample storage 
in a -20°C freezer may be permitted. 
The complete procedure is detailed in the laboratory manual provided by the central laboratory. 
11.0 
ASSESSMENT OF SAFETY 
11.1 
Safety Parameters 
Safety parameters assessed throughout the trial include ECOG performance status; vital signs; 
weight; physical examinations; laboratory parameters; ECG; concomitant medications, and 
adverse events. Any clinically significant change from baseline in a laboratory parameter will be 
reported as an AE. Liver Chemistry Tests, INR, and viral load will be presented as exploratory 
efficacy variables, as will WBC A3AR expression. 
Anticipated toxicities that may occur with CF102 are detailed in Section 4.4 of this protocol as 
well as in the Investigator Brochure (IB). 
11.2 
Duration of Follow-Up 
Any significant clinical adverse event, whether observed by the Investigator or experienced by 
the subject, will be reported beginning with the Cycle 1 Day 1 (Baseline) Visit. Final safety 
evaluations will be performed at the 28-day Follow-Up Visit (28 ± 3 days post End of Dosing)/ 
OL Follow-Up Visit (28 ± 3 days post OL End of Dosing). If the subject begins an alternative 
treatment, then the Follow-Up visit will be performed as soon as possible. Every effort will be 
made to obtain and record survival information for each subject, who will be followed 
indefinitely for survival with, for example, monthly telephone calls. 
If an observed toxicity thought to be at least possibly related to study drug has not resolved by 
the 28-Day Follow-Up Visit/OL Follow-Up Visit, the subject will continue to be followed until 
the event has resolved or stabilized. 
11.3 
Safety Data Review During the Trial 
The Medical Monitor will review safety data on an ongoing basis throughout the trial. 
• 
All serious adverse events (SAEs) must be reported to the Sponsor within 24 hours of the 
Investigator becoming aware of the SAE (Section 11.5). 
• 
Adverse events resulting in a subject’s permanent discontinuation from the trial, regardless 
of seriousness or relationship to study drug, must be promptly reported to the Sponsor. 
• 
The AE pages of each subject’s CRF must be completed and submitted to the Sponsor or 
designee within 2 weeks of each visit. 


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Availability of these data will also enable the Sponsor to notify other participating trial centers 
and regulatory authorities of events occurring during the trial. 
Safety decisions will be documented and communicated in writing to sites. 
11.4 
Adverse Event Definitions/Reporting Requirements 
11.4.1 
Adverse Event 
An AE (also known as an “adverse experience”) is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related (CFR 
312.32). 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the drug, without any 
judgment about causality. 
All clinical AEs noted during the trial will be reported on the appropriate AE page of the CRF 
(paper or electronic). 
11.4.2 
Suspected Adverse Reaction 
A suspected adverse reaction is a subset of all AEs for which there is a reasonable possibility 
(i.e., evidence to suggest a causal relationship between the drug and the AE) that the drug caused 
the event. Suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction. Document suspected adverse reactions on the AE page of the CRF. 
11.4.3 
Adverse Reaction 
An adverse reaction is a subset of all suspected adverse reactions, and is defined as any AE 
caused by a drug. Document any adverse reactions on the AE page of the CRF. 
11.4.4 
Unexpected Adverse Event/Unexpected Suspected Adverse Reaction 
An unexpected AE (or unexpected suspected adverse reaction) is any AE or suspected adverse 
reaction that is not listed in the IB or is not listed at the specificity or severity that has been 
observed, if an IB is not required/available, is not consistent with the risk information described 
in the general investigational plan. This also refers to AEs or suspected adverse reactions 
mentioned in the IB as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the study drug. 


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The Sponsor should be notified within 24 hours of the Investigator becoming aware of the event. 
Document unexpected AEs on the AE page of the CRF. 
11.5 
Serious Adverse Event Definitions/Reporting Requirements 
11.5.1 
Serious Adverse Event or Serious Suspected Adverse Reaction 
An AE or suspected adverse reaction is considered serious if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
1. 
Death. This includes any death that occurs while the subject is enrolled in the trial and/or 
within 30 days after the last dose of study drug. An autopsy will be requested, and if 
performed, results will be submitted to the Sponsor. 
2. 
A life-threatening adverse event. An AE 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 a reaction that had it occurred in a 
more severe form, might have caused death. 
3. 
Inpatient hospitalization or prolongation of existing hospitalization. In the absence of an 
AE, hospitalization or prolongation of hospitalization should not be reported as an SAE in 
the following situations: 
□ 
Hospitalization or prolongation of hospitalization is needed for a procedure required 
by the protocol. 
□ 
Hospitalization or prolongation of hospitalization is part of routine procedure followed 
by trial center. 
□ 
Hospitalization for survey visits or annual physicals. 
□ 
For a hospitalization planned (and documented) before the start of the trial for a pre-
existing condition which has not worsened. 
4. 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
5. 
A congenital anomaly/birth defect. 
6. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
The Sponsor should be notified within 24 hours of the Investigator becoming aware of the event. 
Document SAEs on the AE/SAE page(s) of the CRF. 


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11.5.1.1 
Pregnancy 
For safety reporting purposes, any pregnancy occurring during the trial will be considered an 
“important medical event” (Section 11.5.1). It is not known whether study drug can cause fetal 
harm when administered to a pregnant woman or whether it can affect reproductive capacity. 
There have been no studies in pregnant women. Study drug should only be administered to 
women of childbearing potential when appropriate contraceptive measures have been taken and 
when pregnancy tests are negative. A negative serum β-hCG pregnancy test must be documented 
on the CRF prior to the first dose of study drug and periodically throughout the trial. 
Studies have not been performed to determine whether CF102 affects reproductive function in 
males. Men and women with childbearing potential will be informed as to the unknown risks to a 
pregnancy and will be advised that they must both use effective contraception during the trial 
and for 3 months afterward. Effective birth control includes (a) IUD plus one barrier method, or 
(b) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and 
spermicides. 
If a trial subject becomes pregnant while participating in the trial, the study drug will be 
discontinued immediately and the pregnancy will be reported to the Sponsor. The Investigator 
will then report follow-up information to the Sponsor regarding the course of the pregnancy, 
including perinatal and neonatal outcome, regardless of the fact that the subject has discontinued 
the trial. Once the newborn is determined to be healthy, as defined by and agreed upon by the 
Sponsor and Investigator, additional follow-up will no longer be required. 
11.5.2 
Serious and Unexpected Suspected Adverse Reaction 
A serious and unexpected suspected adverse reaction (SUSAR) is any SAE related to study drug, 
the specificity or severity of which is not consistent with those noted in the current protocol 
and/or IB. This also refers to adverse events or suspected adverse reactions mentioned in the IB 
as occurring with a class of drugs or as anticipated from the pharmacological properties of the 
drug, but are not specifically mentioned as occurring with the study drug. 
The Sponsor should be notified within 24 hours of the Investigator becoming aware of the event. 
Document SUSARs on the AE/SAE page(s) of the CRF. 
11.6 
Recording Adverse Events 
All AEs (including SAEs) are to be accurately recorded on the Adverse Event/Serious Adverse 
Event page(s) of the CRF. The Investigator will carefully evaluate the seriousness, severity, 
duration, and causality of AEs and document the following on the CRF: 


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• 
Severity. In most cases the NCI-CTCAE v4.0 criteria will preferably be used to grade 
severity; however, if an AE is not listed in the CTCAE, the following grading scale may be 
used: Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), Life-Threatening (Grade 4), 
or Fatal (Grade 5). 
• 
Duration of the event. The date of onset, duration of the event, method used to treat the AE, 
and the outcome of the AE should be noted. 
• 
Relationship to study drug: Unrelated, Possibly Related, Probably Related, or Related. 
11.7 
Determining Relationship of Adverse Events to Study Drug 
The following definitions adapted from Karch (1975) will be used to determine the relationship 
of AEs to study drug. 
11.7.1 
Unrelated 
Category applies to adverse events which are clearly felt to be due to extraneous causes (disease, 
environment, etc.) that are unrelated to the study drug. 
11.7.2 
Possibly Related 
The relationship to the study drug can be considered possible if (must have first 2): 
• 
It follows a reasonable temporal sequence from administration of the drug. 
• 
It could readily have been a result of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject. 
• 
It follows a known response pattern to the suspected drug. 
11.7.3 
Probably Related 
The relationship to the study drug can be considered probable if (must have first 3): 
• 
It follows a reasonable temporal sequence from administration of the drug.  
• 
It could not be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors, or other modes of therapy administered to the subject. 
• 
It disappears or decreases upon cessation of drug or reduction in dose.* 
• 
It follows a known response pattern to the suspected drug. 
*There are exceptions when an AE does not disappear upon discontinuation of the drug, yet 
drug relatedness clearly exists, e.g., 1) tardive dyskinesia; 2) fixed drug eruptions. 


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11.7.4 
Related 
The relationship to the study drug can be considered related if (must have first 3): 
• 
It follows a reasonable temporal sequence from administration of the drug or drug levels 
have been established in body fluids or tissues. 
• 
It could not be reasonably explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors, or other modes of therapy administered to the subject. 
• 
It disappears or decreases upon cessation of drug or reduction on dose and appears upon 
rechallenge.* 
• 
It follows a known response pattern to the suspected drug. 
*There are exceptions when an AE does not disappear upon discontinuation of the drug, yet 
drug relatedness clearly exists, e.g., 1) tardive dyskinesia; 2) fixed drug eruptions. 
11.8 
Reporting Deaths and Other Serious Adverse Events 
11.8.1 
Events to Be Reported and Timeframe 
Any death or other serious adverse event experienced by the subject during treatment or within 
30 days of receiving study drug, regardless of relationship to study drug, or any death that occurs 
more than 30 days after receiving study drug and is believed to be study drug-related, must be 
promptly reported to the Sponsor (within 24 hours of the Investigator becoming aware of the 
event) by telephone, telefax, or e-mail transmission. 
11.8.2 
Events Excluded from Expedited Reporting to FDA 
The Sponsor does not plan to report several types of individual SAEs to FDA in an expedited 
manner because they are known consequences of the underlying disease and/or anticipated to 
occur in the trial population at some frequency, independent of drug exposure. These include: 
• 
Progression of the underlying malignancy 
• 
Death due to the underlying malignancy 
• 
Elective hospitalization for transfusion or diagnostic procedure 
• 
Previously scheduled elective surgery 
These events will be reported to FDA/other regulatory authorities and all participating 
Investigators as an IND safety report only if there is evidence, based on an aggregate analysis, to 
suggest a causal relationship between the study drug and the adverse event. 


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11.8.3 
Governing Regulatory Requirements 
Compliance with this request for prompt reporting is essential in that the Sponsor is responsible 
for informing the US Food and Drug Administration (FDA) and other regulatory authorities as 
well as all other participating Investigators of the event. 
Under FDA ruling (US Code of Federal Regulations, Title 21 CFR Part 312.32) and the ICH 
Guidelines for Clinical Safety Data Management Definitions and Standards for Expedited 
Reporting, the Sponsor is required to submit written documentation, in the form of an IND 
Safety Report, on the following: 
• 
SUSARs. 
• 
Unexpected fatal or life-threatening suspected adverse reactions. 
• 
Findings from other studies that suggest a significant risk to humans exposed to drug. 
• 
Findings from animal or in vitro testing that suggest a significant risk to humans exposed to 
drug. 
• 
Increased rate of occurrence of serious suspected adverse reactions from what is reported in 
the Investigator Brochure or the protocol. 
Written submission must be made by the Sponsor to the FDA/other regulatory authorities (and 
by the Investigator to the IRB/EC) as soon as possible, and in no event later than 15 calendar 
days after the Sponsor determines that the information qualifies for reporting. The Sponsor shall 
also inform all Investigators. 
In addition, the Sponsor is further required to report, by either telephone or facsimile 
transmission or in writing to the FDA/other regulatory authorities the occurrence of any 
unexpected fatal or life-threatening event associated with the use of the drug (SUSARs) no later 
than 7 calendar days after notification of the event, followed by a written report no later than 
15 calendar days after the initial report receipt date. The Sponsor shall also inform all 
Investigators. 
The Sponsor will provide expedited reports of the following SUSARs to Investigators for 
reporting to their IRB/EC: 
• 
SUSARs that have arisen in the clinical trial that was assessed by the IRB/EC. 
• 
SUSARs that have arisen in other clinical trials of the same Sponsor and with the same 
medicinal product, and that could have consequences for the safety of the subjects involved 
in the clinical trial that was assessed by the IRB/EC. 


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Investigators are required to promptly report to the IRB/EC all unanticipated problems involving 
risk to human subjects, including adverse events that should be considered unanticipated 
problems (21 CFR 312.53(c)(1)(vii), 312.66, and 21 CFR 56.108(b)(1)). 
11.8.4 
Initial Information Provided by the Investigator 
The Investigator must transmit sufficient initial information to the Sponsor (or designee) should 
an SAE report meet the criteria for completion of an IND Safety Report. As much of the 
following information about the subject and the event will be requested: 
• 
Subject identification code, gender, and age or date of birth 
• 
Underlying diagnosis and extent of disease 
• 
Lot number and expiration date of study drug (if available) 
• 
Dose, route, frequency, and duration of study drug administered 
• 
Date of study drug administration 
• 
Description of event, including date of onset and duration 
• 
Date of death (if applicable) 
• 
Intervention(s) required 
• 
Concomitant therapy (including regimens and indications) 
• 
Pertinent laboratory data/diagnostic study (including dates) 
• 
Pertinent medical history 
• 
Study drug status (dose interrupted, discontinued) 
• 
Did event abate after interruption of study drug administration (if applicable)? 
• 
Did event recur after study drug was reintroduced (if applicable)? 
• 
Severity of the AE 
• 
Relationship of the AE to study treatment 
• 
Outcome of the AE 
11.8.5 
Follow-up Information 
Follow-up data concerning the SAE (e.g., diagnostic test reports, physician's summaries, etc.) 
must also be submitted to the Sponsor as they become available, preferably by telefax or e-mail, 
as soon as they become available, and until the event resolves or stabilizes. 
11.9 
SAE and SUSAR Review and Potential Impact on Trial Conduct 
The Investigator will review each SAE report and evaluate further the relationship of the SAE to 
study drug and to the subject’s underlying disease. 


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Based on the Investigator’s and Sponsor’s assessment of causality of the adverse event and 
discussions with the Medical Monitor, a decision will be made by the Sponsor concerning the 
need for further action with respect to the future conduct of the trial. The primary consideration 
governing further action is whether new findings affect the safety of other subjects participating 
in the clinical trial. If the discovery of a new AE related to study drug raises concern over the 
safety of its continued administration to subjects, the Sponsor will take immediate steps to notify 
FDA, other regulatory authorities, and all Investigators participating in clinical trials with the 
study drug. 
Further action required may include any of the following: 
• 
Alteration of the existing research program by modification of the protocol. 
• 
Discontinuation or suspension of the trial. 
• 
Alteration of the informed consent process by modification of the existing consent form and 
informing current trial participants of new findings. 
• 
Modification of previously identified expected suspected adverse reaction lists to include 
adverse events newly identified as study drug-related. 
12.0 
STATISTICAL METHODS AND PLANNED ANALYSES 
12.1 
General Considerations 
This is a multicenter, randomized, double-blind, placebo-controlled trial in subjects with 
advanced HCC and CPB cirrhosis whose disease has progressed while taking 1 prior systemic 
drug therapy for HCC. The trial will evaluate the efficacy and safety of CF102 as compared to 
placebo. Subjects will be randomly assigned in a 2:1 ratio to treatment with oral doses of either 
CF102 25 mg or matching placebo administered BID for consecutive, 28-day cycles. Subjects 
will be evaluated regularly for safety including changes in laboratory parameters, vital signs, 
physical examination, ECOG PS, and ECG assessments compared to baseline findings. 
Treatment will continue until the subject experiences unacceptable drug-related intolerability. 
Subjects will return for a follow-up visit 28 days after completion of the last dose of study drug. 
Subjects who discontinue will be followed indefinitely for survival status. 
The primary efficacy endpoint will be OS, defined as the number of days from first dose to death 
due to any cause. Secondary endpoints to be evaluated are TTP, PFS, OR consisting of CR or PR 
for subjects who enter the trial with measurable disease by RECIST v1.1, and DC which includes 
both subjects with OR as well as those with SD. Survival status will be assessed continuously. 
Tumor status will be assessed at the Pre-Study Visit and every 8 weeks thereafter (i.e., at the end 
of even-numbered cycles) by CT scan or MRI according to RECIST v1.1 (Appendix A, 


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Eisenhauer, 2009 [as modified by Santoro 2013]). Liver Chemistry Tests, INR, and viral load 
will be presented as exploratory efficacy variables, as will WBC adenosine A3 receptor 
expression. PK blood samples collected on Day 1 of Cycles 1 and 2 and trough samples collected 
on Days 8 and 15 of Cycle 1 will be used to generate a composite PK profile for subjects 
receiving CF102 treatment, and allow exploratory analysis of exposure-response for this trial. 
12.2 
Sample Size Determination 
Approximately 78 subjects will be enrolled and randomized to either CF102 or placebo using a 
2:1 randomization. The post-accrual treatment period was originally planned to continue until a 
total of 75 deaths have been recorded. Assuming a hazard ratio of 0.5, 75 events will provide 
80% power for the logrank test at level 0.05 (two-sided). It is assumed that the 78 subjects will 
be enrolled in approximately 78 weeks and the trial will continue for a total of 104 weeks (SiZ: 
Logrank Test with Given Accrual Duration and Study Duration, Version 2.0, Cytel, Inc. 2011). 
The required number of deaths and the required number of subjects are reasonably stable with 
respect to the duration of accrual and length of the post-accrual follow-up period, being between 
70 and 80, to have power of 80% for an assumed hazard rate of 0.5, especially for studies with a 
post-accrual follow-up period. 
12.3 
Trial Populations 
12.3.1 
Safety Population 
The Safety Population will consist of all randomized subjects who received at least 1 dose of 
CF102 or placebo. 
12.3.2 
Intent-to-Treat (ITT) Population 
The Intent-to-Treat (ITT) Population will consist of all subjects in the Safety Population who 
have any post-Baseline efficacy data, including Liver Chemistry Tests and/or INR on Day 8 of 
Cycle 1, or death or discontinuation due to disease progression at any time. 
12.3.3 
Per Protocol (PP) Population 
The Per Protocol (PP) Population will consist of all subjects in the ITT Population with no major 
protocol deviations, including major violations of inclusion and exclusion criteria and violation 
of RECIST requirements regarding the number of target lesions at Screening. Exclusion of 
subjects from the PP Population will be determined prior to unblinding. Tumor response will be 
analyzed for the PP Population. 


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12.3.4 
Pharmacokinetic Population 
The Pharmacokinetic Population will consist of all subjects with at least 1 on-treatment PK 
sample for analysis. 
12.4 
Data Analyses 
12.4.1 
Subject Accountability, Demographics, and Baseline Characteristics 
Subject completion status, dose reductions, and terminations from the trial will be summarized 
for each of the treatment cycles and for the trial overall. Subjects with major protocol violations 
will be listed. Demographics will be summarized along with baseline characteristics such as 
medical history, PE, vital signs, and concomitant medications. Subjects in the Safety Population 
who are excluded from either the ITT Population or the PP Population will be identified. 
12.4.2 
Efficacy Data 
All efficacy analyses will be performed for the ITT Population. Tumor response will be analyzed 
for the PP Population, with the analyses for the ITT Population being primary. 
Time to event variables will be summarized using the number observed, number censored, 
median, and 25th and 75th percentiles from Kaplan-Meier curves. Data will be summarized 
using descriptive statistics (number of subjects (n), mean, median, standard deviation, minimum, 
and maximum) for continuous variables. Categorical variables will be summarized using 
frequencies and percentages. 
Between-treatment comparisons with respect to OS, TTP, and PFS will be performed using 
logrank tests, with Cox’s proportional hazards regression model used for supportive analyses to 
assess the impact of covariates. Tumor lesion measurements and changes from baseline will be 
summarized by cycle and treatment. Objective response rates and DC rates will be presented and 
between-treatment comparisons will be performed using the normal approximation to the 
binomial distribution by treatment for each even-numbered cycle. Between-treatment 
comparisons with respect to AFP will be performed using Analysis of Covariance (ANCOVA) 
with the value at baseline value used as a covariate and frequencies of subjects with AFP levels 
<20, 20-200, or >200 ng/mL will be presented by treatment for each cycle. 
Liver Chemistry Tests, INR, and viral load will be summarized using descriptive statistics and 
clinically significant abnormalities will be listed. Additionally, between-treatment comparisons 
with respect to these laboratory parameters will be performed using ANCOVA with the baseline 
value used as a covariate. 


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The relationship between WBC A3AR expression and clinical response will be assessed by 
providing the counts and percentages for Overall Response by Change from Baseline (CFB) in 
A3AR expression categorized as less than or at least the median by treatment at each visit. 
12.4.3 
Safety Data 
Safety observations and measurements including study drug exposure, adverse events, laboratory 
data, physical examination findings, vital signs, ECG, and ECOG PS will be summarized and 
presented in tables and listings. 
Laboratory parameters including thyroid functions will be summarized using descriptive 
statistics and data listings of clinically significant abnormalities. Physical examinations, vital 
signs, ECOG PS, and ECG data will be summarized by changes from baseline values for each 
treatment using descriptive statistics. Liver Chemistry Tests, INR, and viral load will be 
presented as exploratory efficacy variables. 
Adverse events will be coded using the MedDRA™ dictionary. The number and percentages of 
subjects experiencing AEs will be tabulated by system organ class and preferred term. 
Assessments of AEs will include characterization of the type, incidence, severity, seriousness, 
and relationship to treatment. Summary subject listings will be provided for subjects with dose 
interruptions and dose reductions, SAEs, AEs resulting in discontinuation from the trial, and 
deaths. Adverse events will be graded according to NCI-CTCAE criteria, version 4.0. 
12.4.4 
Pharmacokinetics Data 
A PK and exploratory PK-PD analysis plan will be prepared and finalized prior to database lock. 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
Before enrolling any subjects in this trial, a Sponsor representative and the Investigator will 
review the protocol, Investigator Brochure, CRFs and instructions for their completion, as well 
as the procedures for obtaining informed consent and for reporting AEs and SAEs. A qualified 
representative of the Sponsor monitors the conduct of the trial by visiting the site and by 
contacting the site by telephone and e-mail. During site visits, the trial monitor will assure 
accurate and reliable data collection by verifying the information recorded on the CRFs (paper or 
electronic) against source documents and medical records (i.e., source document verification). 
All data will be entered into a trial database for analysis and reporting. Upon completion of data 
entry, the database will receive a quality assurance comprehensive validation check to ensure 
acceptable accuracy and completeness. 


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A comprehensive validation check will verify the data and discrepancy reports will be generated 
for resolution by the Investigator. 
A Data Management Plan, which includes an Edit Specifications Document, will be prepared 
and updated as necessary through the course of the trial. 
14.0 
DOCUMENTATION AND INSPECTIONS 
14.1 
Trial Monitoring 
The Sponsor has responsibility to governing regulatory authorities to take all reasonable steps to 
ensure the proper conduct of the trial with respect to trial ethics, protocol adherence, and data 
integrity and validity. 
This trial will be closely monitored by Sponsor representatives throughout its duration. 
Monitoring will be in the form of personal visits with the Investigator and their staff as well as 
any appropriate communications by telephone, telefax, mail, or e-mail transmission. The purpose 
of these contacts is to review progress of the trial, Investigator and subject adherence to protocol 
requirements, and determine if there are any problems associated with the conduct of the trial. 
The following may be assessed during site monitoring visits: 
• 
Required regulatory documentation 
• 
Signed informed consent documents 
• 
Subject accrual and follow up 
• 
Study drug inventory records 
• 
Investigator and subject compliance to the trial protocol 
• 
Concomitant therapy use 
• 
Adverse event documentation 
• 
Protocol deviation and violation documentation 
• 
Data is accurate, complete, and verifiable when compared to source documents 
The Investigator and site staff are expected to cooperate with monitors during such visits and 
provide them with all relevant trial documents. 
14.2 
Audits and Inspections 
All documentation pertaining to this clinical trial may be subject to a quality assurance audit by 
personnel designated by Can-Fite BioPharma, Ltd., the FDA, or other regulatory agencies with 
similar responsibilities. Upon request, the auditor will have access for inspection, copying, 
review, and audit of all source documentation, CRFs, medical records, correspondence, and 


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informed consent documents pertaining to the subjects in the trial. The Investigator agrees to 
promptly take any reasonable steps that are regulated by the Sponsor as a result of an audit to 
cure deficiencies in the trial documentation and CRFs. Other documentation subject to quality 
assurance audit includes the Investigator's IRB/EC files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the trial maintained in any 
supporting pharmacy facilities. Conditions of storage of study materials are also subject to 
inspection. Representatives of Can-Fite may observe conduct of any aspect of the clinical trial or 
its supporting activities both within and outside of the Investigator's institution. 
15.0 
ETHICAL AND LEGAL ISSUES 
15.1 
Ethical Conduct/Good Clinical Practice 
This trial will be conducted in accordance with the ethical principles that have their origin in the 
current Declaration of Helsinki and will be consistent with International Conference on 
Harmonization Good Clinical Practice (ICH GCP) and applicable regulatory requirements. 
15.2 
Institutional Review Board (IRB) and Ethics Committee (EC) 
This trial must be reviewed and approved by the IRB/EC representing each participating 
institution prior to enrolling subjects. Each IRB/EC must be appropriately constituted and meet 
all requirements as described in Part 56, Title 21 of the Code of Federal Regulations. The review 
must include both the protocol and the informed consent document for the trial. A copy of the 
Letter or Notice of Approval from the IRB/EC must be received by Can-Fite prior to shipment of 
drug supplies to the Investigator. The IRB/EC membership list must be submitted to Can-Fite 
with the written IRB/EC approval and updated lists, if applicable. 
The Investigator must promptly report all changes in the research activity and all unanticipated 
problems involving risk to the subjects or others to their IRB/EC. The Investigator will provide 
progress reports as required by the IRB/EC. The Investigator is responsible for assuring 
continuing review and approval of the clinical trial on an annual basis and submitting 
documentation of renewal to the Sponsor. The Investigator will give notice to the IRB/EC when 
participation in the trial has been completed. 
15.3 
Written Informed Consent 
The Investigator agrees to protect the rights, safety, and welfare of the subjects entered into the 
trial, including obtaining written informed consent prior to performing any trial-related 
procedures and informing each subject that the study drug is being used for investigational 


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purposes. A copy of the IRB/EC-approved consent form to be used during the trial must be 
submitted for Sponsor review prior to initiation of the trial. 
Prior to entry into the trial, the purpose and nature of the trial and possible adverse effects must 
be explained to each subject. All questions about the trial should be answered to the subject’s 
satisfaction or the subject’s legal representative. It is the responsibility of the Investigator or 
designee to obtain written informed consent from each subject, thereby attesting that consent was 
freely given. An Investigator listed on the Form FDA 1572 will then co-sign the informed 
consent document. A copy of the signed and dated consent form will be given to the subject. 
Documentation of the informed consent process must be evident in the subject’s clinical files, 
and the original executed consent form must be available for review by the trial monitor. 
15.3.1 
Update of Informed Consent 
In the event that modifications in the experimental design, dosages, parameters, subject selection, 
etc., of the protocol are indicated or required, and in the event that such modifications 
substantially alter the trial design or increase the potential risk to subjects, the Investigator will 
prepare a revision to the existing informed consent document. Such a revision will be reviewed 
and approved by the appropriate IRB/EC, and documentation of this approval will be forwarded 
to the Sponsor for submission to the appropriate regulatory body. 
In addition, all current as well as future trial participants will be informed of the trial design 
modification or increase in potential risk, and written informed consent will be obtained as 
outlined above (Section 15.3). 
15.4 
Records and CRFs 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated with the study drug. Data reported on the CRF (which may be either paper or 
electronic) that are derived from source documents must be consistent with the source documents 
or the discrepancies must be explained. 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirements. 
The completed CRF must be promptly reviewed, signed, and dated by a qualified physician who 
is an Investigator or Sub-Investigator. The Investigator must retain a copy of the CRFs including 
records of the changes and corrections. 


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15.5 
Modification of the Trial Protocol 
The trial is to be conducted as described in this protocol. Under no circumstances should the 
protocol be modified for any subject without the prior consent of the Sponsor and, if necessary, 
the IRB/EC responsible at the investigative site. 
In the event that modifications in the experimental design, dosages, parameters, subject selection, 
etc., of the protocol are indicated or required, such changes will only be instituted following 
consultation between the Sponsor and Investigator and will be accomplished through formal 
amendment to this protocol and approval by the appropriate IRB/EC, except when necessary to 
immediately eliminate apparent hazards to subjects. Any amendment prepared by the Sponsor 
will be submitted to the FDA/other regulatory authorities and to the appropriate IRB/EC, and 
will be made part of the protocol. 
15.6 
Termination of the Trial 
Should the Sponsor and/or the Investigator(s) discover conditions, during the course of the trial, 
that indicate that it should be discontinued, an appropriate procedure for termination will be 
instituted. 
15.7 
Retention of Records 
United States federal law requires that the Investigator retain copies of all files pertaining to the 
trial (i.e., medical records, laboratory reports, drug inventory/disposition records, signed 
informed consent forms, CRFs, all correspondence, dates and reports of monitoring visits) for a 
period of 2 years following the date of marketing application approval of the drug for the 
indication investigated in the trial, and until there is no pending or contemplated marketing 
application, or for 2 years following the Sponsor’s discontinuing worldwide clinical development 
of the study drug, as notified by the Sponsor, whichever is longer. 
If the Investigator relocates, retires, or withdraws for any reason from the trial, the records may 
be transferred to an acceptable designee, such as another Investigator within the institution. Prior 
notice of such transfer will be provided in writing to the Sponsor. The Investigator must obtain 
written permission from the Sponsor prior to disposing of any records. 


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16.0 
PUBLICATION POLICY 
The Investigator and the institution understand and agree that participation in a multicenter trial 
involves a commitment to publish the trial data in a cooperative publication prior to publication 
or oral presentation of trial results on an individual basis. Upon completion or early termination 
of the trial and Sponsor evaluation of all data from the trial, the Investigator or institution may 
publish or disclose the results of the trial, provided a copy of the proposed publication is sent to 
the Sponsor for review at least 60 days prior to the date of submission for publication or of 
public disclosure. The Sponsor will complete its review within the 60 days and will have 
authority to require that the institution and/or the Investigator delete any reference to confidential 
information (other than the results) from the disclosure. 
If during the review period, the Sponsor notifies the institution that it desires patent applications 
to be filed on any Sponsor’s inventions disclosed or contained in the disclosures, the institution 
and the Investigator will defer publication or other disclosure for a period not to exceed an 
additional 60 days, sufficient to permit the Sponsor to file any desired patent applications. 
No submission for publication or public disclosure by the institution or the Investigator will be 
made until results from all centers have been received and analyzed by the Sponsor, or the multi-
center trial has been terminated or abandoned at all centers. If a publications committee, or a 
committee of Investigators, is formed for publication of results of the multicenter clinical trial, 
any separate publication by the institution or the Investigator will be delayed until the initial 
publication by the committee or a determination has been made by the committee not to make 
such publication. 
17.0 
INVESTIGATOR RESPONSIBILITIES 
An Investigator conducting a clinical trial with an investigational agent is required to comply 
with regulations described in the US Code of Federal Regulations, Title 21 CFR Part 312, ICH 
Good Clinical Practice guidelines, as well as local laws and regulations. 
The Investigator: 
• 
Will personally conduct or supervise the conduct of the trial. The Investigator will ensure 
that all Sub-Investigators and others assisting in the trial are adequately informed about the 
protocol, the study drug, and their trial-related duties and functions. 
• 
Will make changes to the conduct of the trial only after receiving the Sponsor’s approval, 
except to protect the safety, rights, or welfare of subjects. 


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• 
Will not disclose any goods, materials, information (oral or written) and unpublished 
documentation provided by the Sponsor (including this protocol, the subject CRFs, and the 
IB) to any unauthorized person without the Sponsor’s prior written consent. 
• 
Will maintain a Subject Screening Log listing all subjects entered into the trial, those 
considered for trial entry and subsequently excluded, and the reason for exclusion. 
• 
Will store study drug in a secure location, under the conditions indicated in Section 8.0, and 
will maintain a drug inventory form. Will destroy used supplies in an appropriate manner 
according to institutional policy and document such destruction. At the completion of the 
trial, the Investigator will return all unused trial materials to the Sponsor, unless otherwise 
authorized in writing. 
• 
Will record trial data on CRFs (paper or electronic) provided by the contract research 
organization (CRO) for each subject who receives any amount of study drug, including 
those who withdraw before completion of the trial. Will ensure the accuracy, completeness, 
and timeliness of the data reported on the CRF and in required reports. Will review CRFs 
for completeness and accuracy prior to submission for data entry, and will sign and date the 
CRF. 
• 
Will maintain adequate and accurate records for each subject dosed with study drug. Will 
include source documents such as hospital, clinic, or office charts; laboratory reports; trial 
worksheets; and signed informed consent documents in the Investigator’s files along with 
subject trial records. Will include in the consent form a statement allowing the Sponsor (or 
designee), as well as authorized regulatory agencies, to have direct access to source data 
that support data reported on the CRF. 
• 
Will provide the Sponsor with the normal laboratory ranges for the laboratories to be used 
in the trial as well as the laboratory certification number. Will provide copies of any 
additional records pertinent to the trial (e.g., radiology reports, chart summaries, autopsy 
reports) to the Sponsor or regulatory authorities, if requested, with due precaution taken to 
ensure subject confidentiality. 
• 
Will maintain subject confidentiality at all times during the trial by using coded identifiers 
when referring to a particular subject (including in any publications). 
• 
Will inform subjects that the study drug is being used for investigational purposes. 
• 
Will report to the Sponsor any AEs that occur during the trial in accordance with ICH, CFR 
21 Part 312.64 and local laws. 
 


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18.0 
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function. Clin Transl Oncol. 2013 Feb; 15(2): 146-153. 
 


Can-Fite BioPharma, Ltd. 
Protocol CF102-201HCC, Amendment 5 
Confidential 
6 November 2018 
 
70 
APPENDIX A: RECIST RESPONSE CRITERIA (V1.1) 
NOTE: RECIST v 1.1 as modified by Santoro [2013]: 
Up to 5 target lesions in the liver and 2 target lesions in other organs are measured. 
RATIONALE: Because HCC often presents as a multifocal disease in the liver and the standard RECIST 
limitation to a maximum of 2 target lesions in the liver was considered too restrictive for a study with 
time to progression as the primary endpoint. 
 
 


New response evaluation criteria in solid tumours:
Revised RECIST guideline (version 1.1)
E.A. Eisenhauera,*, P. Therasseb, J. Bogaertsc, L.H. Schwartzd, D. Sargente, R. Fordf,
J. Danceyg, S. Arbuckh, S. Gwytheri, M. Mooneyg, L. Rubinsteing, L. Shankarg, L. Doddg,
R. Kaplanj, D. Lacombec, J. Verweijk
aNational Cancer Institute of Canada – Clinical Trials Group, 10 Stuart Street, Queen’s University, Kingston, ON, Canada
bGlaxoSmithKline Biologicals, Rixensart, Belgium
cEuropean Organisation for Research and Treatment of Cancer, Data Centre, Brussels, Belgium
dMemorial Sloan Kettering Cancer Center, New York, NY, USA
eMayo Clinic, Rochester, MN, USA
fRadPharm, Princeton, NJ, USA
gDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
hSchering-Plough, Kenilworth, NJ, USA
iEast Surrey Hospital, Redhill, Surrey, UK
jNational Cancer Research Network, Leeds, UK
kErasmus University Medical Center, Rotterdam, The Netherlands
A R T I C L E
I N F O
Article history:
Received 17 October 2008
Accepted 29 October 2008
Keywords:
Response criteria
Solid tumours
Guidelines
A B S T R A C T
Background: Assessment of the change in tumour burden is an important feature of the
clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response)
and disease progression are useful endpoints in clinical trials. Since RECIST was published
in 2000, many investigators, cooperative groups, industry and government authorities have
adopted these criteria in the assessment of treatment outcomes. However, a number of
questions and issues have arisen which have led to the development of a revised RECIST
guideline (version 1.1). Evidence for changes, summarised in separate papers in this special
issue, has come from assessment of a large data warehouse (>6500 patients), simulation
studies and literature reviews.
Highlights of revised RECIST 1.1: Major changes include: Number of lesions to be assessed: based
on evidence from numerous trial databases merged into a data warehouse for analysis pur-
poses, the number of lesions required to assess tumour burden for response determination
has been reduced from a maximum of 10 to a maximum of ﬁve total (and from ﬁve to two
per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes
with a short axis of P15 mm are considered measurable and assessable as target lesions.
The short axis measurement should be included in the sum of lesions in calculation of
tumour response. Nodes that shrink to <10 mm short axis are considered normal. Conﬁrma-
tion of response is required for trials with response primary endpoint but is no longer
required in randomised studies since the control arm serves as appropriate means of inter-
pretation of data. Disease progression is clariﬁed in several aspects: in addition to the previ-
ous deﬁnition of progression in target disease of 20% increase in sum, a 5 mm absolute
increase is now required as well to guard against over calling PD when the total sum is very
0959-8049/$ - see front matter  2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejca.2008.10.026
* Corresponding author: Tel.: +1 613 533 6430; fax: +1 613 533 2411.
E-mail address: eeisenhauer@ctg.queensu.ca (E.A. Eisenhauer).
E U R O P E A N J O U R N A L O F C A N C E R 4 5 ( 2 0 0 9 ) 2 2 8 –2 4 7
available at www.sciencedirect.com
journal homepage: www.ejconline.com


small. Furthermore, there is guidance offered on what constitutes ‘unequivocal progres-
sion’ of non-measurable/non-target disease, a source of confusion in the original RECIST
guideline. Finally, a section on detection of new lesions, including the interpretation of
FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a
new imaging appendix with updated recommendations on the optimal anatomical assess-
ment of lesions.
Future work: A key question considered by the RECIST Working Group in developing RECIST
1.1 was whether it was appropriate to move from anatomic unidimensional assessment of
tumour burden to either volumetric anatomical assessment or to functional assessment
with PET or MRI. It was concluded that, at present, there is not sufﬁcient standardisation
or evidence to abandon anatomical assessment of tumour burden. The only exception to
this is in the use of FDG-PET imaging as an adjunct to determination of progression. As
is detailed in the ﬁnal paper in this special issue, the use of these promising newer
approaches requires appropriate clinical validation studies.
 2008 Elsevier Ltd. All rights reserved.
1.
Background
1.1.
History of RECIST criteria
Assessment of the change in tumour burden is an important
feature of the clinical evaluation of cancer therapeutics. Both
tumour shrinkage (objective response) and time to the devel-
opment of disease progression are important endpoints in
cancer clinical trials. The use of tumour regression as the
endpoint for phase II trials screening new agents for evi-
dence of anti-tumour effect is supported by years of evi-
dence suggesting that, for many solid tumours, agents
which produce tumour shrinkage in a proportion of patients
have a reasonable (albeit imperfect) chance of subsequently
demonstrating an improvement in overall survival or other
time to event measures in randomised phase III studies (re-
viewed in [1–4]). At the current time objective response car-
ries with it a body of evidence greater than for any other
biomarker supporting its utility as a measure of promising
treatment effect in phase II screening trials. Furthermore,
at both the phase II and phase III stage of drug development,
clinical trials in advanced disease settings are increasingly
utilising time to progression (or progression-free survival)
as an endpoint upon which efﬁcacy conclusions are drawn,
which is also based on anatomical measurement of tumour
size.
However, both of these tumour endpoints, objective re-
sponse and time to disease progression, are useful only if
based on widely accepted and readily applied standard crite-
ria based on anatomical tumour burden. In 1981 the World
Health Organisation (WHO) ﬁrst published tumour response
criteria, mainly for use in trials where tumour response was
the primary endpoint. The WHO criteria introduced the con-
cept of an overall assessment of tumour burden by summing
the products of bidimensional lesion measurements and
determined response to therapy by evaluation of change from
baseline while on treatment.5 However, in the decades that
followed their publication, cooperative groups and pharma-
ceutical companies that used the WHO criteria often ‘modi-
ﬁed’ them to accommodate new technologies or to address
areas that were unclear in the original document. This led
to confusion in interpretation of trial results6 and in fact,
the application of varying response criteria was shown to lead
to very different conclusions about the efﬁcacy of the same
regimen.7 In response to these problems, an International
Working Party was formed in the mid 1990s to standardise
and simplify response criteria. New criteria, known as RECIST
(Response Evaluation Criteria in Solid Tumours), were pub-
lished in 2000.8 Key features of the original RECIST include
deﬁnitions of minimum size of measurable lesions, instruc-
tions on how many lesions to follow (up to 10; a maximum
ﬁve per organ site), and the use of unidimensional, rather
than bidimensional, measures for overall evaluation of tu-
mour burden. These criteria have subsequently been widely
adopted by academic institutions, cooperative groups, and
industry for trials where the primary endpoints are objective
response or progression. In addition, regulatory authorities
accept
RECIST
as
an
appropriate
guideline
for
these
assessments.
1.2.
Why update RECIST?
Since RECIST was published in 2000, many investigators have
conﬁrmed in prospective analyses the validity of substituting
unidimensional for bidimensional (and even three-dimen-
sional)-based criteria (reviewed in [9]). With rare exceptions
(e.g. mesothelioma), the use of unidimensional criteria seems
to perform well in solid tumour phase II studies.
However, a number of questions and issues have arisen
which merit answers and further clarity. Amongst these
are whether fewer than 10 lesions can be assessed without
affecting the overall assigned response for patients (or the
conclusion about activity in trials); how to apply RECIST in
randomised phase III trials where progression, not response,
is the primary endpoint particularly if not all patients have
measurable disease; whether or how to utilise newer imag-
ing technologies such as FDG-PET and MRI; how to handle
assessment of lymph nodes; whether response conﬁrmation
is truly needed; and, not least, the applicability of RECIST in
trials of targeted non-cytotoxic drugs. This revision of the
RECIST guidelines includes updates that touch on all these
points.
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229


1.3.
Process of RECIST 1.1 development
The RECIST Working Group, consisting of clinicians with
expertise in early drug development from academic research
organisations, government and industry, together with imag-
ing specialists and statisticians, has met regularly to set the
agenda for an update to RECIST, determine the evidence
needed to justify the various changes made, and to review
emerging evidence. A critical aspect of the revision process
was to create a database of prospectively documented solid
tumour measurement data obtained from industry and aca-
demic group trials. This database, assembled at the EORTC
Data Centre under the leadership of Jan Bogaerts and Patrick
Therasse (co-authors of this guideline), consists of >6500 pa-
tients with >18,000 target lesions and was utilised to investi-
gate the impact of a variety of questions (e.g. number of
target lesions required, the need for response conﬁrmation,
and lymph node measurement rules) on response and pro-
gression-free survival outcomes. The results of this work,
which after evaluation by the RECIST Working Group led to
most of the changes in this revised guideline, are reported
in detail in a separate paper in this special issue.10 Larry Sch-
wartz and Robert Ford (also co-authors of this guideline) also
provided key databases from which inferences have been
made that inform these revisions.11
The publication of this revised guideline is believed to be
timely since it incorporates changes to simplify, optimise
and standardise the assessment of tumour burden in clinical
trials. A summary of key changes is found in Appendix I. Be-
cause the fundamental approach to assessment remains
grounded in the anatomical, rather than functional, assess-
ment of disease, we have elected to name this version RECIST
1.1, rather than 2.0.
1.4.
What about volumetric or functional assessment?
This raises the question, frequently posed, about whether it is
‘time’ to move from anatomic unidimensional assessment of
tumour burden to either volumetric anatomical assessment
or to functional assessment (e.g. dynamic contrast enhanced
MRI or CT or (18)F-ﬂuorodeoxyglucose positron emission
tomographic (FDG-PET) techniques assessing tumour metab-
olism). As can be seen, the Working Group and particularly
those involved in imaging research, did not believe that there
is at present sufﬁcient standardisation and widespread avail-
ability to recommend adoption of these alternative assess-
ment methods. The only exception to this is in the use of
FDG-PET imaging as an adjunct to determination of progres-
sion, as described later in this guideline. As detailed in paper
in this special issue12, we believe that the use of these prom-
ising newer approaches (which could either add to or substitute
for anatomical assessment as described in RECIST) requires
appropriate and rigorous clinical validation studies. This pa-
per by Sargent et al. illustrates the type of data that will be
needed to be able to deﬁne ‘endpoints’ for these modalities
and how to determine where and when such criteria/modal-
ities can be used to improve the reliability with which truly
active new agents are identiﬁed and truly inactive new agents
are discarded in comparison to RECIST criteria in phase II
screening trials. The RECIST Working Group looks forward
to such data emerging in the next few years to allow the
appropriate changes to the next iteration of the RECIST
criteria.
2.
Purpose of this guideline
This guideline describes a standard approach to solid tumour
measurement and deﬁnitions for objective assessment of
change in tumour size for use in adult and paediatric cancer
clinical trials. It is expected these criteria will be useful in all
trials where objective response is the primary study endpoint,
as well as in trials where assessment of stable disease, tu-
mour progression or time to progression analyses are under-
taken, since all of these outcome measures are based on an
assessment of anatomical tumour burden and its change on
study. There are no assumptions in this paper about the pro-
portion of patients meeting the criteria for any of these end-
points which will signal that an agent or treatment regimen is
active: those deﬁnitions are dependent on type of cancer in
which a trial is being undertaken and the speciﬁc agent(s) un-
der study. Protocols must include appropriate statistical sec-
tions which deﬁne the efﬁcacy parameters upon which the
trial sample size and decision criteria are based. In addition
to providing deﬁnitions and criteria for assessment of tumour
response,
this
guideline
also
makes
recommendations
regarding standard reporting of the results of trials that utilise
tumour response as an endpoint.
While these guidelines may be applied in malignant brain
tumour studies, there are also separate criteria published for
response assessment in that setting.13 This guideline is not in-
tended for use for studies of malignant lymphoma since
international guidelines for response assessment in lym-
phoma are published separately.14
Finally, many oncologists in their daily clinical practice fol-
low their patients’ malignant disease by means of repeated
imaging studies and make decisions about continued therapy
on the basis of both objective and symptomatic criteria. It is
not intended that these RECIST guidelines play a role in that
decision making, except if determined appropriate by the
treating oncologist.
3.
Measurability of tumour at baseline
3.1.
Deﬁnitions
At baseline, tumour lesions/lymph nodes will be categorised
measurable or non-measurable as follows:
3.1.1.
Measurable
Tumour lesions: Must be accurately measured in at least one
dimension (longest diameter in the plane of measurement is
to be recorded) with a minimum size of:
• 10 mm by CT scan (CT scan slice thickness no greater than
5 mm; see Appendix II on imaging guidance).
• 10 mm caliper measurement by clinical exam (lesions
which cannot be accurately measured with calipers should
be recorded as non-measurable).
• 20 mm by chest X-ray.
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Malignant lymph nodes: To be considered pathologically en-
larged and measurable, a lymph node must be P15 mm in
short axis when assessed by CT scan (CT scan slice thickness
recommended to be no greater than 5 mm). At baseline and in
follow-up, only the short axis will be measured and followed
(see Schwartz et al. in this Special Issue15). See also notes be-
low on ‘Baseline documentation of target and non-target le-
sions’ for information on lymph node measurement.
3.1.2.
Non-measurable
All other lesions, including small lesions (longest diameter
<10 mm or pathological lymph nodes with P10 to <15 mm
short axis) as well as truly non-measurable lesions. Lesions
considered truly non-measurable include: leptomeningeal dis-
ease, ascites, pleural or pericardial effusion, inﬂammatory
breast disease, lymphangitic involvement of skin or lung,
abdominal masses/abdominal organomegaly identiﬁed by
physical exam that is not measurable by reproducible imaging
techniques.
3.1.3.
Special considerations regarding lesion measurability
Bone lesions, cystic lesions, and lesions previously treated
with local therapy require particular comment:
Bone lesions:.
• Bone scan, PET scan or plain ﬁlms are not considered ade-
quate imaging techniques to measure bone lesions. How-
ever,
these
techniques
can
be
used
to
conﬁrm
the
presence or disappearance of bone lesions.
• Lytic bone lesions or mixed lytic-blastic lesions, with identi-
ﬁable soft tissue components, that can be evaluated by cross
sectional imaging techniques such as CT or MRI can be con-
sidered as measurable lesions if the soft tissue component
meets the deﬁnition of measurability described above.
• Blastic bone lesions are non-measurable.
Cystic lesions:.
• Lesions that meet the criteria for radiographically deﬁned
simple cysts should not be considered as malignant lesions
(neither measurable nor non-measurable) since they are, by
deﬁnition, simple cysts.
• ‘Cystic lesions’ thought to represent cystic metastases can
be considered as measurable lesions, if they meet the deﬁ-
nition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are pre-
ferred for selection as target lesions.
Lesions with prior local treatment:.
• Tumour lesions situated in a previously irradiated area, or
in an area subjected to other loco-regional therapy, are usu-
ally not considered measurable unless there has been dem-
onstrated progression in the lesion. Study protocols should
detail the conditions under which such lesions would be
considered measurable.
3.2.
Speciﬁcations by methods of measurements
3.2.1.
Measurement of lesions
All measurements should be recorded in metric notation,
using calipers if clinically assessed. All baseline evaluations
should be performed as close as possible to the treatment
start and never more than 4 weeks before the beginning of
the treatment.
3.2.2.
Method of assessment
The same method of assessment and the same technique
should be used to characterise each identiﬁed and reported
lesion at baseline and during follow-up. Imaging based evalu-
ation should always be done rather than clinical examination
unless the lesion(s) being followed cannot be imaged but are
assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered mea-
surable when they are superﬁcial and P10 mm diameter as
assessed using calipers (e.g. skin nodules). For the case of skin
lesions, documentation by colour photography including a ru-
ler to estimate the size of the lesion is suggested. As noted
above, when lesions can be evaluated by both clinical exam
and imaging, imaging evaluation should be undertaken since
it is more objective and may also be reviewed at the end of the
study.
Chest X-ray: Chest CT is preferred over chest X-ray, particu-
larly when progression is an important endpoint, since CT is
more sensitive than X-ray, particularly in identifying new le-
sions. However, lesions on chest X-ray may be considered
measurable if they are clearly deﬁned and surrounded by aer-
ated lung. See Appendix II for more details.
CT, MRI: CT is the best currently available and reproducible
method to measure lesions selected for response assessment.
This guideline has deﬁned measurability of lesions on CT
scan based on the assumption that CT slice thickness is
5 mm or less. As is described in Appendix II, when CT scans
have slice thickness greater than 5 mm, the minimum size
for a measurable lesion should be twice the slice thickness.
MRI is also acceptable in certain situations (e.g. for body
scans). More details concerning the use of both CT and MRI
for assessment of objective tumour response evaluation are
provided in Appendix II.
Ultrasound: Ultrasound is not useful in assessment of lesion
size and should not be used as a method of measurement.
Ultrasound examinations cannot be reproduced in their en-
tirety for independent review at a later date and, because
they are operator dependent, it cannot be guaranteed that
the same technique and measurements will be taken from
one assessment to the next (described in greater detail in
Appendix II). If new lesions are identiﬁed by ultrasound in
the course of the study, conﬁrmation by CT or MRI is ad-
vised. If there is concern about radiation exposure at CT,
MRI may be used instead of CT in selected instances.
Endoscopy, laparoscopy: The utilisation of these techniques for
objective tumour evaluation is not advised. However, they
can be useful to conﬁrm complete pathological response
when biopsies are obtained or to determine relapse in trials
where recurrence following complete response or surgical
resection is an endpoint.
Tumour markers: Tumour markers alone cannot be used to as-
sess objective tumour response. If markers are initially above
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231


the upper normal limit, however, they must normalise for a
patient to be considered in complete response. Because
tumour markers are disease speciﬁc, instructions for their
measurement should be incorporated into protocols on a
disease speciﬁc basis. Speciﬁc guidelines for both CA-125
response (in recurrent ovarian cancer) and PSA response (in
recurrent prostate cancer), have been published.16–18 In addi-
tion, the Gynecologic Cancer Intergroup has developed CA125
progression criteria which are to be integrated with objective
tumour assessment for use in ﬁrst-line trials in ovarian
cancer.19
Cytology, histology: These techniques can be used to differenti-
ate between PR and CR in rare cases if required by protocol
(for example, residual lesions in tumour types such as germ
cell tumours, where known residual benign tumours can re-
main). When effusions are known to be a potential adverse
effect of treatment (e.g. with certain taxane compounds or
angiogenesis inhibitors), the cytological conﬁrmation of the
neoplastic origin of any effusion that appears or worsens dur-
ing treatment can be considered if the measurable tumour
has met criteria for response or stable disease in order to dif-
ferentiate between response (or stable disease) and progres-
sive disease.
4.
Tumour response evaluation
4.1.
Assessment of overall tumour burden and
measurable disease
To assess objective response or future progression, it is nec-
essary to estimate the overall tumour burden at baseline and
use this as a comparator for subsequent measurements.
Only patients with measurable disease at baseline should
be included in protocols where objective tumour response
is the primary endpoint. Measurable disease is deﬁned by
the presence of at least one measurable lesion (as detailed
above in Section 3). In studies where the primary endpoint
is tumour progression (either time to progression or propor-
tion with progression at a ﬁxed date), the protocol must
specify if entry is restricted to those with measurable disease
or whether patients having non-measurable disease only are
also eligible.
4.2.
Baseline documentation of ‘target’ and ‘non-target’
lesions
When more than one measurable lesion is present at baseline
all lesions up to a maximum of ﬁve lesions total (and a max-
imum of two lesions per organ) representative of all involved
organs should be identiﬁed as target lesions and will be re-
corded and measured at baseline (this means in instances
where patients have only one or two organ sites involved a
maximum of two and four lesions respectively will be re-
corded). For evidence to support the selection of only ﬁve tar-
get lesions, see analyses on a large prospective database in
the article by Bogaerts et al.10.
Target lesions should be selected on the basis of their size
(lesions with the longest diameter), be representative of all in-
volved organs, but in addition should be those that lend
themselves to reproducible repeated measurements. It may be
the case that, on occasion, the largest lesion does not lend it-
self to reproducible measurement in which circumstance the
next largest lesion which can be measured reproducibly
should be selected. To illustrate this point see the example
in Fig. 3 of Appendix II.
Lymph nodes merit special mention since they are normal
anatomical structures which may be visible by imaging even
if not involved by tumour. As noted in Section 3, pathological
nodes which are deﬁned as measurable and may be identi-
ﬁed as target lesions must meet the criterion of a short axis
of P15 mm by CT scan. Only the short axis of these nodes
will contribute to the baseline sum. The short axis of the
node is the diameter normally used by radiologists to judge
if a node is involved by solid tumour. Nodal size is normally
reported as two dimensions in the plane in which the image
is obtained (for CT scan this is almost always the axial plane;
for MRI the plane of acquisition may be axial, saggital or
coronal). The smaller of these measures is the short axis.
For example, an abdominal node which is reported as being
20 mm · 30 mm has a short axis of 20 mm and qualiﬁes as a
malignant, measurable node. In this example, 20 mm should
be recorded as the node measurement (See also the example
in Fig. 4 in Appendix II). All other pathological nodes (those
with short axis P10 mm but <15 mm) should be considered
non-target lesions. Nodes that have a short axis <10 mm
are considered non-pathological and should not be recorded
or followed.
A sum of the diameters (longest for non-nodal lesions, short
axis for nodal lesions) for all target lesions will be calculated
and reported as the baseline sum diameters. If lymph nodes
are to be included in the sum, then as noted above, only the
short axis is added into the sum. The baseline sum diameters
will be used as reference to further characterise any objective
tumour regression in the measurable dimension of the
disease.
All other lesions (or sites of disease) including pathological
lymph nodes should be identiﬁed as non-target lesions and
should also be recorded at baseline. Measurements are not re-
quired and these lesions should be followed as ‘present’, ‘ab-
sent’, or in rare cases ‘unequivocal progression’ (more details
to follow). In addition, it is possible to record multiple non-
target lesions involving the same organ as a single item on
the case record form (e.g. ‘multiple enlarged pelvic lymph
nodes’ or ‘multiple liver metastases’).
4.3.
Response criteria
This section provides the deﬁnitions of the criteria used to
determine objective tumour response for target lesions.
4.3.1.
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions.
Any pathological lymph nodes (whether target or
non-target) must have reduction in short axis to
<10 mm.
Partial Response (PR): At least a 30% decrease in the sum of
diameters of target lesions, taking as reference the
baseline sum diameters.
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Progressive Disease (PD): At least a 20% increase in the sum
of diameters of target lesions, taking as reference
the smallest sum on study (this includes the baseline
sum if that is the smallest on study). In addition to
the relative increase of 20%, the sum must also dem-
onstrate an absolute increase of at least 5 mm. (Note:
the appearance of one or more new lesions is also
considered progression).
Stable Disease (SD): Neither sufﬁcient shrinkage to qualify for
PR nor sufﬁcient increase to qualify for PD, taking as
reference the smallest sum diameters while on study.
4.3.2.
Special notes on the assessment of target lesions
Lymph nodes. Lymph nodes identiﬁed as target lesions should
always have the actual short axis measurement recorded (mea-
sured in the same anatomical plane as the baseline examina-
tion), even if the nodes regress to below 10 mm on study. This
means that when lymph nodes are included as target lesions,
the ‘sum’ of lesions may not be zero even if complete response
criteria are met, since a normal lymph node is deﬁned as having
a short axis of <10 mm. Case report forms or other data collec-
tion methods may therefore be designed to have target nodal le-
sions recorded in a separate section where, in order to qualify
for CR, each node must achieve a short axis <10 mm. For PR,
SD and PD, the actual short axis measurement of the nodes is
to be included in the sum of target lesions.
Target lesions that become ‘too small to measure’. While on
study, all lesions (nodal and non-nodal) recorded at baseline
should have their actual measurements recorded at each sub-
sequent evaluation, even when very small (e.g. 2 mm). How-
ever, sometimes lesions or lymph nodes which are recorded
as target lesions at baseline become so faint on CT scan that
the radiologist may not feel comfortable assigning an exact
measure and may report them as being ‘too small to measure’.
When this occurs it is important that a value be recorded on
the case report form. If it is the opinion of the radiologist that
the lesion has likely disappeared, the measurement should be
recorded as 0 mm. If the lesion is believed to be present and is
faintly seen but too small to measure, a default value of 5 mm
should be assigned (Note: It is less likely that this rule will be
used for lymph nodes since they usually have a deﬁnable size
when normal and are frequently surrounded by fat such as in
the retroperitoneum; however, if a lymph node is believed to
be present and is faintly seen but too small to measure, a de-
fault value of 5 mm should be assigned in this circumstance as
well). This default value is derived from the 5 mm CT slice
thickness (but should not be changed with varying CT slice
thickness). The measurement of these lesions is potentially
non-reproducible, therefore providing this default value will
prevent false responses or progressions based upon measure-
ment error. To reiterate, however, if the radiologist is able to
provide an actual measure, that should be recorded, even if
it is below 5 mm.
Lesions that split or coalesce on treatment. As noted in Appen-
dix II, when non-nodal lesions ‘fragment’, the longest diame-
ters of the fragmented portions should be added together to
calculate the target lesion sum. Similarly, as lesions coalesce,
a plane between them may be maintained that would aid in
obtaining maximal diameter measurements of each individ-
ual lesion. If the lesions have truly coalesced such that they
are no longer separable, the vector of the longest diameter
in this instance should be the maximal longest diameter for
the ‘coalesced lesion’.
4.3.3.
Evaluation of non-target lesions
Thissection provides the deﬁnitionsofthe criteriausedtodeter-
mine the tumour response for the group of non-target lesions.
While some non-target lesions may actually be measurable,
they need not be measured and instead should be assessed only
qualitatively at the time points speciﬁed in the protocol.
Complete Response (CR): Disappearance of all non-target le-
sions and normalisation of tumour marker level. All
lymph nodes must be non-pathological in size
(<10 mm short axis).
Non-CR/Non-PD: Persistence of one or more non-target le-
sion(s) and/or maintenance of tumour marker level
above the normal limits.
Progressive Disease (PD): Unequivocal progression (see com-
ments below) of existing non-target lesions. (Note:
the appearance of one or more new lesions is also
considered progression).
4.3.4.
Special notes on assessment of progression of non-
target disease
The concept of progression of non-target disease requires
additional explanation as follows:
When the patient also has measurable disease. In this setting,
to achieve ‘unequivocal progression’ on the basis of the
non-target disease, there must be an overall level of substan-
tial worsening in non-target disease such that, even in pres-
ence of SD or PR in target disease, the overall tumour
burden has increased sufﬁciently to merit discontinuation
of therapy (see examples in Appendix II and further details
below). A modest ‘increase’ in the size of one or more non-tar-
get lesions is usually not sufﬁcient to quality for unequivocal
progression status. The designation of overall progression so-
lely on the basis of change in non-target disease in the face of
SD or PR of target disease will therefore be extremely rare.
When the patient has only non-measurable disease.This circum-
stance arises in some phase III trials when it is not a criterion of
study entry to have measurable disease. The same general con-
cepts apply here as noted above, however, in this instance there
is no measurable disease assessment to factor into the inter-
pretation of an increase in non-measurable disease burden.
Because worsening in non-target disease cannot be easily
quantiﬁed (by deﬁnition: if all lesions are truly non-measur-
able) a useful test that can be applied when assessing patients
for unequivocal progression is to consider if the increase in
overall disease burden based on the change in non-measurable
disease is comparable in magnitude to the increase that would
berequiredtodeclarePDformeasurabledisease: i.e.anincrease
in tumour burden representing an additional 73% increase in
‘volume’ (which is equivalent to a 20% increase diameter in a
measurable lesion). Examples include an increase in a pleural
effusion from ‘trace’ to ‘large’, an increase in lymphangitic
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233


disease from localised to widespread, or may be described in
protocols as ‘sufﬁcient to require a change in therapy’. Some
illustrative examples are shown in Figs. 5 and 6 in Appendix II.
If ‘unequivocal progression’ is seen, the patient should be con-
sidered to have had overall PD at that point. While it would be
ideal to have objective criteria to apply to non-measurable dis-
ease, the very nature of that disease makes it impossible to do
so, therefore the increase must be substantial.
4.3.5.
New lesions
The appearance of new malignant lesions denotes disease
progression; therefore, some comments on detection of new
lesions are important. There are no speciﬁc criteria for the
identiﬁcation of new radiographic lesions; however, the ﬁnd-
ing of a new lesion should be unequivocal: i.e. not attributable
to differences in scanning technique, change in imaging
modality or ﬁndings thought to represent something other
than tumour (for example, some ‘new’ bone lesions may be
simply healing or ﬂare of pre-existing lesions). This is partic-
ularly important when the patient’s baseline lesions show
partial or complete response. For example, necrosis of a liver
lesion may be reported on a CT scan report as a ‘new’ cystic
lesion, which it is not.
A lesion identiﬁed on a follow-up study in an anatomical
location that was not scanned at baseline is considered a new
lesion andwill indicate diseaseprogression. An example of this
is the patient who has visceral disease at baseline and while on
study has a CTor MRI brain ordered which reveals metastases.
The patient’s brain metastases are considered to be evidence of
PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its
small size, continued therapy and follow-up evaluation will
clarify if it represents truly new disease. If repeat scans con-
ﬁrm there is deﬁnitely a new lesion, then progression should
be declared using the date of the initial scan.
While FDG-PET response assessments need additional
study, it is sometimes reasonable to incorporate the use of
FDG-PET scanning to complement CT scanning in assessment
of progression (particularly possible ‘new’ disease). New le-
sions on the basis of FDG-PET imaging can be identiﬁed
according to the following algorithm:
a. Negative FDG-PET at baseline, with a positivel FDG-PET
at follow-up is a sign of PD based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at fol-
low-up:
If the positive FDG-PET at follow-up corresponds to a
new site of disease conﬁrmed by CT, this is PD.
If the positive FDG-PET at follow-up is not conﬁrmed as
a new site of disease on CT, additional follow-up CT
scans are needed to determine if there is truly progres-
sion occurring at that site (if so, the date of PD will be
the date of the initial abnormal FDG-PET scan).
If the positive FDG-PET at follow-up corresponds to a
pre-existing site of disease on CT that is not progress-
ing on the basis of the anatomic images, this is not PD.
4.4.
Evaluation of best overall response
The best overall response is the best response recorded from
the start of the study treatment until the end of treatment
taking into account any requirement for conﬁrmation. On oc-
casion a response may not be documented until after the end
of therapy so protocols should be clear if post-treatment
assessments are to be considered in determination of best
overall response. Protocols must specify how any new therapy
introduced before progression will affect best response desig-
nation. The patient’s best overall response assignment will
depend on the ﬁndings of both target and non-target disease
and will also take into consideration the appearance of new
lesions. Furthermore, depending on the nature of the study
and the protocol requirements, it may also require conﬁrma-
tory measurement (see Section 4.6). Speciﬁcally, in non-ran-
domised trials where response is the primary endpoint,
conﬁrmation of PR or CR is needed to deem either one the
‘best overall response’. This is described further below.
4.4.1.
Time point response
It is assumed that at each protocol speciﬁed time point, a re-
sponse assessment occurs. Table 1 on the next page provides
a summary of the overall response status calculation at each
time point for patients who have measurable disease at
baseline.
When patients have non-measurable (therefore non-tar-
get) disease only, Table 2 is to be used.
4.4.2.
Missing assessments and inevaluable designation
When no imaging/measurement is done at all at a particular
time point, the patient is not evaluable (NE) at that time point.
If only a subset of lesion measurements are made at an
assessment, usually the case is also considered NE at that
time point, unless a convincing argument can be made that
the contribution of the individual missing lesion(s) would
not change the assigned time point response. This would be
most likely to happen in the case of PD. For example, if a pa-
tient had a baseline sum of 50 mm with three measured le-
sions and at follow-up only two lesions were assessed, but
those gave a sum of 80 mm, the patient will have achieved
PD status, regardless of the contribution of the missing lesion.
4.4.3.
Best overall response: all time points
The best overall response is determined once all the data for the
patient is known.
Best response determination in trials where conﬁrmation of com-
plete or partial response IS NOT required: Best response in these
trials is deﬁned as the best response across all time points (for
example, a patient who has SD at ﬁrst assessment, PR at sec-
ond assessment, and PD on last assessment has a best overall
response of PR). When SD is believed to be best response, it
must also meet the protocol speciﬁed minimum time from
baseline. If the minimum time is not met when SD is other-
wise the best time point response, the patient’s best response
depends on the subsequent assessments. For example, a pa-
tient who has SD at ﬁrst assessment, PD at second and does
not meet minimum duration for SD, will have a best response
of PD. The same patient lost to follow-up after the ﬁrst SD
assessment would be considered inevaluable.
l A ‘positive’ FDG-PET scan lesion means one which is FDG avid
with an uptake greater than twice that of the surrounding tissue
on the attenuation corrected image.
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Best response determination in trials where conﬁrmation of com-
plete or partial response IS required: Complete or partial re-
sponses may be claimed only if the criteria for each are met
at a subsequent time point as speciﬁed in the protocol (gener-
ally 4 weeks later). In this circumstance, the best overall re-
sponse can be interpreted as in Table 3.
4.4.4.
Special notes on response assessment
When nodal disease is included in the sum of target lesions
and the nodes decrease to ‘normal’ size (<10 mm), they may
still have a measurement reported on scans. This measure-
ment should be recorded even though the nodes are normal
in order not to overstate progression should it be based on
increase in size of the nodes. As noted earlier, this means that
patients with CR may not have a total sum of ‘zero’ on the
case report form (CRF).
In trials where conﬁrmation of response is required, re-
peated ‘NE’ time point assessments may complicate best re-
sponse determination. The analysis plan for the trial must
address how missing data/assessments will be addressed in
determination of response and progression. For example, in
most trials it is reasonable to consider a patient with time
point responses of PR-NE-PR as a conﬁrmed response.
Patients with a global deterioration of health status requir-
ing discontinuation of treatment without objective evidence
of disease progression at that time should be reported as
‘symptomatic deterioration’. Every effort should be made to
document objective progression even after discontinuation
of treatment. Symptomatic deterioration is not a descriptor
of an objective response: it is a reason for stopping study ther-
apy. The objective response status of such patients is to be
determined by evaluation of target and non-target disease
as shown in Tables 1–3.
Conditions that deﬁne ‘early progression, early death and
inevaluability’ are study speciﬁc and should be clearly de-
scribed in each protocol (depending on treatment duration,
treatment periodicity).
In some circumstances it may be difﬁcult to distinguish
residual disease from normal tissue. When the evaluation of
complete response depends upon this determination, it is
recommended that the residual lesion be investigated (ﬁne
Table 3 – Best overall response when conﬁrmation of CR and PR required.
Overall response
Overall response
BEST overall response
First time point
Subsequent time point
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable.
a If a CR is truly met at ﬁrst time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to baseline,
makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether minimum duration
for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and in fact the
patient had PR, not CR at the ﬁrst time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
Table 1 – Time point response: patients with target (+/–
non-target) disease.
Target lesions
Non-target lesions
New
lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or
not all evaluated
No
PR
SD
Non-PD or
not all evaluated
No
SD
Not all
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease,
PD = progressive disease, and NE = inevaluable.
Table 2 – Time point response: patients with non-target
disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete
response,
PD = progressive
disease,
and
NE = inevaluable.
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target
disease since SD is increasingly used as endpoint for assessment
of efﬁcacy in some trials so to assign this category when no
lesions can be measured is not advised.
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235


needle aspirate/biopsy) before assigning a status of complete
response. FDG-PET may be used to upgrade a response to a CR
in a manner similar to a biopsy in cases where a residual
radiographic abnormality is thought to represent ﬁbrosis or
scarring. The use of FDG-PET in this circumstance should be
prospectively described in the protocol and supported by dis-
ease speciﬁc medical literature for the indication. However, it
must be acknowledged that both approaches may lead to
false positive CR due to limitations of FDG-PETand biopsy res-
olution/sensitivity.
For equivocal ﬁndings of progression (e.g. very small and
uncertain new lesions; cystic changes or necrosis in existing
lesions), treatment may continue until the next scheduled
assessment. If at the next scheduled assessment, progression
is conﬁrmed, the date of progression should be the earlier
date when progression was suspected.
4.5.
Frequency of tumour re-evaluation
Frequency
of
tumour
re-evaluation
while
on
treatment
should be protocol speciﬁc and adapted to the type and sche-
dule of treatment. However, in the context of phase II studies
where the beneﬁcial effect of therapy is not known, follow-up
every 6–8 weeks (timed to coincide with the end of a cycle) is
reasonable. Smaller or greater time intervals than these could
be justiﬁed in speciﬁc regimens or circumstances. The proto-
col should specify which organ sites are to be evaluated at
baseline (usually those most likely to be involved with meta-
static disease for the tumour type under study) and how often
evaluations are repeated. Normally, all target and non-target
sites are evaluated at each assessment. In selected circum-
stances certain non-target organs may be evaluated less fre-
quently. For example, bone scans may need to be repeated
only when complete response is identiﬁed in target disease
or when progression in bone is suspected.
After the end of the treatment, the need for repetitive tu-
mour evaluations depends on whether the trial has as a goal
the response rate or the time to an event (progression/death).
If ‘time to an event’ (e.g. time to progression, disease-free
survival, progression-free survival) is the main endpoint of
the study, then routine scheduled re-evaluation of protocol
speciﬁed sites of disease is warranted. In randomised com-
parative trials in particular, the scheduled assessments
should be performed as identiﬁed on a calendar schedule
(for example: every 6–8 weeks on treatment or every 3–4
months after treatment) and should not be affected by delays
in therapy, drug holidays or any other events that might lead
to imbalance in a treatment arm in the timing of disease
assessment.
4.6.
Conﬁrmatory measurement/duration of response
4.6.1.
Conﬁrmation
In non-randomised trials where response is the primary end-
point, conﬁrmation of PR and CR is required to ensure re-
sponses identiﬁed are not the result of measurement error.
This will also permit appropriate interpretation of results in
the context of historical data where response has traditionally
required conﬁrmation in such trials (see the paper by Bogaerts
et al. in this Special Issue10). However, in all other circum-
stances, i.e. in randomised trials (phase II or III) or studies
where stable disease or progression are the primary endpoints,
conﬁrmation ofresponseis notrequiredsince itwillnotaddva-
lue to theinterpretationoftrial results.However, eliminationof
the requirement for response conﬁrmation may increase the
importance of central review to protect against bias, in partic-
ular in studies which are not blinded.
In the case of SD, measurements must have met the SD
criteria at least once after study entry at a minimum interval
(in general not less than 6–8 weeks) that is deﬁned in the
study protocol.
4.6.2.
Duration of overall response
The duration of overall response is measured from the time
measurement criteria are ﬁrst met for CR/PR (whichever is ﬁrst
recorded) until the ﬁrst date that recurrent or progressive dis-
ease is objectively documented (taking as reference for progres-
sive disease the smallest measurements recorded on study).
The duration of overall complete response is measured
from the time measurement criteria are ﬁrst met for CR until
the ﬁrst date that recurrent disease is objectively documented.
4.6.3.
Duration of stable disease
Stable disease is measured from the start of the treatment (in
randomised trials, from date of randomisation) until the crite-
ria for progression are met, taking as reference the smallest
sum on study (if the baseline sum is the smallest, this is the
reference for calculation of PD).
The clinical relevance of the duration of stable disease var-
ies in different studies and diseases. If the proportion of pa-
tients achieving stable disease for a minimum period of time
is an endpoint of importance in a particular trial, the protocol
should specify the minimal time interval required between
two measurements for determination of stable disease.
Note: The duration of response and stable disease as well as
theprogression-free survivalareinﬂuencedby thefrequencyof
follow-up after baseline evaluation. It is not in the scope of this
guideline to deﬁne a standard follow-up frequency. The fre-
quency should take into account many parameters including
disease types and stages, treatment periodicity and standard
practice. However, these limitations of the precision of the
measured endpoint should be taken into account if compari-
sons between trials are to be made.
4.7.
Progression-free survival/proportion progression-free
4.7.1.
Phase II trials
This guideline is focused primarily on the use of objective re-
sponse endpoints for phase II trials. In some circumstances, ‘re-
sponse rate’ may not be the optimal method to assess the
potential anticancer activity of new agents/regimens. In such
cases ‘progression-free survival’ (PFS) or the ‘proportion pro-
gression-free’ at landmark time points, might be considered
appropriate alternatives to provide an initial signal of biologic
effect of new agents. It is clear, however, that in an uncontrolled
trial, these measures are subject to criticism since an appar-
ently promising observation may be related to biological factors
such as patient selectionand not theimpactof theintervention.
Thus, phase II screening trials utilising these endpoints are best
designed with a randomised control. Exceptions may exist
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where the behaviour patterns of certain cancers are so consis-
tent (and usually consistently poor), that a non-randomised
trial is justiﬁable (see for example van Glabbeke et al.20). How-
ever, in these cases it will be essential to document with care
the basis for estimating the expected PFS or proportion progres-
sion-free in the absence of a treatment effect.
4.7.2.
Phase III trials
Phase III trials in advanced cancers are increasingly designed
to evaluate progression-free survival or time to progression as
the primary outcome of interest. Assessment of progression
is relatively straightforward if the protocol requires all pa-
tients to have measurable disease. However, restricting entry
to this subset of patients is subject to criticism: it may result
in a trial where the results are less likely to be generalisable if,
in the disease under study, a substantial proportion of pa-
tients would be excluded. Moreover, the restriction to entry
will slow recruitment to the study. Increasingly, therefore, tri-
als allow entry of both patients with measurable disease as
well as those with non-measurable disease only. In this cir-
cumstance, care must be taken to explicitly describe the ﬁnd-
ings which would qualify for progressive disease for those
patients without measurable lesions. Furthermore, in this set-
ting, protocols must indicate if the maximum number of re-
corded target lesions for those patients with measurable
disease may be relaxed from ﬁve to three (based on the data
found in Bogaerts et al.10 and Moskowitz et al.11). As found in
the ‘special notes on assessment of progression’, these guide-
lines offer recommendations for assessment of progression
in this setting. Furthermore, if available, validated tumour mar-
ker measures of progression (as has been proposed for ovarian
cancer) may be useful to integrate into the deﬁnition of pro-
gression. Centralised blinded review of imaging studies or of
source imaging reports to verify ‘unequivocal progression’
may be needed if important drug development or drug ap-
proval decisions are to be based on the study outcome. Finally,
as noted earlier, because the date of progression is subject to
ascertainment bias, timing of investigations in study arms
should be the same. The article by Dancey et al. in this special
issue21 provides a more detailed discussion of the assessment
of progression in randomised trials.
4.8.
Independent review of response and progression
For trials where objective response (CR + PR) is the primary end-
point, and in particular where key drug development deci-
sions are based on the observation of a minimum number of
responders, it is recommended that all claimed responses be
reviewed by an expert(s) independent of the study. If the study
is a randomised trial, ideally reviewers should be blinded to
treatment assignment. Simultaneous review of the patients’
ﬁles and radiological images is the best approach.
Independent review of progression presents some more
complex issues: for example, there are statistical problems
with the use of central-review-based progression time in
place of investigator-based progression time due to the poten-
tial introduction of informative censoring when the former
precedes the latter. An overview of these factors and other
lessons learned from independent review is provided in an
article by Ford et al. in this special issue.22
4.9.
Reporting best response results
4.9.1.
Phase II trials
When response is the primary endpoint, and thus all patients
must have measurable disease to enter the trial, all patients
included in the study must be accounted for in the report of
the results, even if there are major protocol treatment devia-
tions or if they are not evaluable. Each patient will be assigned
one of the following categories:
1. Complete response
2. Partial response
3. Stable disease
4. Progression
5. Inevaluable for response: specify reasons (for example: early
death, malignant disease; early death, toxicity; tumour
assessments not repeated/incomplete; other (specify)).
Normally, all eligible patients should be included in the
denominator for the calculation of the response rate for phase
II trials (in some protocols it will be appropriate to include all
treated patients). It is generally preferred that 95% two-sided
conﬁdence limits are given for the calculated response rate.
Trial conclusions should be based on the response rate for
all eligible (or all treated) patients and should not be based
on a selected ‘evaluable’ subset.
4.9.2.
Phase III trials
Response evaluation in phase III trials may be an indicator
of the relative anti-tumour activity of the treatments eval-
uated and is almost always a secondary endpoint. Ob-
served differences in response rate may not predict the
clinically relevant therapeutic beneﬁt for the population
studied. If objective response is selected as a primary end-
point for a phase III study (only in circumstances where a
direct relationship between objective tumour response and
a clinically relevant therapeutic beneﬁt can be unambigu-
ously demonstrated for the population studied), the same
criteria as those applying to phase II trials should be used
and all patients entered should have at least one measur-
able lesion.
In those many cases where response is a secondary end-
point and not all trial patients have measurable disease, the
method for reporting overall best response rates must be
pre-speciﬁed in the protocol. In practice, response rate may
be reported using either an ‘intent to treat’ analysis (all ran-
domised patients in the denominator) or an analysis where
only the subset of patients with measurable disease at
baseline are included. The protocol should clearly specify
how response results will be reported, including any subset
analyses that are planned.
The original version of RECIST suggested that in phase III
trials one could write protocols using a ‘relaxed’ interpreta-
tion of the RECIST guidelines (for example, reducing the num-
ber of lesions measured) but this should no longer be done
since these revised guidelines have been amended in such a
way that it is clear how these criteria should be applied for
all trials in which anatomical assessment of tumour response
or progression are endpoints.
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237


Appendix I. Summary of major changes RECIST 1.0 to RECIST 1.1
RECIST 1.0
RECIST 1.1
Rationale
Reference in special issue
(if applicable)
Minimum size measurable
lesions
CT: 10 mm spiral
CT 10 mm; delete reference to
spiral scan
Most scans used have 5 mm or less slice
thickness Clearer to give instruction based on
slice interval if it is greater than 5 mm
20 mm non-spiral
Clinical: 20 mm
Clinical: 10 mm (must be
measurable with calipers)
Caliper measurement will make this reliable
Lymph node: not mentioned
CT:
Since nodes are normal structure need to deﬁne
pathological enlargement. Short axis is most
sensitive
Schwartz et al.15
P15 mm short axis for target
P10–<15 mm for non-target
<10 mm is non-pathological
Special considerations on
lesion measurability
–
Notes included on bone
lesions, cystic lesions
Clarify frequently asked questions
Overall tumour burden
10 lesions (5 per organ)
5 lesions (2 per organ)
Data warehouse analysis shows no loss of
information if lesion number reduced from 10 to
5. A maximum of 2 lesions per organ yields
sufﬁcient representation per disease site
Bogaerts et al.10
Response criteria target
disease
CR lymph node not mentioned
CR lymph nodes must be
<10 mm short axis
In keeping with normal size of nodes
Schwartz et al.15
PD 20% increase over smallest sum on
study or new lesions
PD 20% increase over smallest
sum on study (including
baseline if that is smallest) and
at least 5 mm increase or new
lesions
Clariﬁcation that if baseline measurement is
smaller than any on study measurement, it is
reference against which PD is assessed
5 mm absolute increase to guard against over
calling PD when total sum is very small and 20%
increase is within measurement error
Response criteria non-target
disease
‘unequivocal progression’ considered as PD
More detailed description of
‘unequivocal progression’ to
indicate that it should not
normally trump target disease
status. It must be
representative of overall
disease status change, not a
single lesion increase
Confusion with RECIST 1.0 where some were
considering PD if ‘increase’ in any non-target
lesion, even when target disease is stable or
responding
New lesions
–
New section on New lesions
To provide guidance on when a lesion is
considered new (and thus PD)
Overall response
Table integrated target and non-target
lesions
Two tables: one integrating
target and non-target and the
other of non-target only
To account for the fact that RECIST criteria are
now being used in trials where PFS is the
endpoint and not all patients have measurable
(target) disease at baseline
Dancey et al.21
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RECIST 1.0
RECIST 1.1
Rationale
Reference in special issue
(if applicable)
Special notes:
Frequently asked questions on these topics
How to assess and measure
lymph nodes
CR in face of residual tissue
Discussion of ‘equivocal’
progression
Conﬁrmatory measure
For CR and PR: criteria
must be met again 4
weeks after initial
documentation
Retain this requirement ONLY
for
non-randomised trials with
primary endpoint of response
Data warehouse shows that response rates
rise when conﬁrmation is eliminated, but
the only circumstance where this is
important is in trials where there is no
concurrent comparative control and where
this measure is the primary endpoint
Bogaerts et al.10
Progression-free survival
General comments only
More speciﬁc comments on
use of PFS (or proportion
progression-free) as
phase II endpoint
Increasing use of PFS in phase III trials
requires guidance on assessment of PD in
patients with non-measurable disease
Dancey et al.21
Greater detail on PFS
assessment in phase III trials
Reporting of response
results
9 categories suggested for
reporting phase II results
Divided into phase II and phase
III
Simpliﬁes reporting and clariﬁes how to
report phase II and III data consistently
9 categories collapsed into 5
In phase III, guidance given
about reporting response
Response in phase III
trials
More relaxed guidelines
possible if protocol speciﬁed
This section removed and
referenced in section
above: no need to have
different criteria for phase II
and III
Simpliﬁcation of response assessment by
reducing number of lesions and eliminating
need for conﬁrmation in randomised
studies where response is not the primary
endpoint makes separate ‘rules’
unnecessary
Imaging appendix
Appendix I
Appendix II: updated with
detailed guidance on
use of MRI, PET/CT
Evolving use of newer modalities addressed.
Enhanced guidance in response to frequent
questions and from radiology review
experience
Other practical guidance
included
New appendices
Appendix I: comparison of
RECIST 1.0 and 1.1
Appendix III: frequently asked
questions
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239


Conﬂict of interest statement
None declared.
Acknowledgements
The RECIST Working Group would like to thank the following
organisations which made data bases available to us in order
to perform the analyses which informed decisions about
changes to this version of the criteria: Amgen; AstraZeneca;
Breast Cancer International Research Group (BCIRG); Bristol-
Myers
Squibb; European
Organisation for
Research and
Treatment of Cancer (EORTC) Breast Cancer Group and Gas-
trointestinal
Group;
Erasmus
University
Medical
Center,
Rotterdam, The Netherlands; Genentech; Pﬁzer; RadPharm;
Roche; SanoﬁAventis.
We would also like to thank the following individuals from
academic, government, and pharmaceutical organisations for
providing helpful comments on an earlierdraft of these revised
guidelines: Ohad Amit, Phil Murphy, Teri Crofts and Janet Be-
gun, GlaxoSmithKline, USA; Laurence H. Baker, Southwest
Oncology Group, USA; Karla Ballman, Mayo Clinic, USA;
Charles Baum, Darrel Cohen, and Mary Ashford Collier, Pﬁzer,
USA; Gary J. Becker, American Board of Radiology, Tucson,
USA; Jean-Yves Blay, University Claude Pertrand, Lyon France;
Renzo Canetta, Bristol-Myers Squibb, USA; David Chang, Am-
gen Inc., USA; Sandra Chica, Perceptive Informations Inc. (PAR-
EXEL),
USA;
Martin
Edelman,
University
of
Maryland
Greenbaum Cancer Centre, USA; Gwendolyn Fyfe, Genentech,
USA; Bruce Giantonio, Eastern Cooperative Oncology Group,
USA; Gary Gordon, Abbott Pharmaceuticals, USA; Ronald Gott-
lieb, Roswell Park Cancer Institute, USA; Simon Kao, University
of Iowa College of Medicine, USA; Wasaburo Koizumi, Kitasato
University, Japan; Alessandro Riva, Novartis Pharmaceuticals,
USA; Wayne Rackhoff, Ortho Biotech Oncology Research and
Development, USA; Nagahiro Saijo, President Japanese Society
of Medical Oncology, Japan; Mitchell Schnall American College
of Radiology Imaging Network, USA; Yoshik Shimamura, PAR-
EXEL International Inc., Japan; Rajeshwari Sridhara, Centre
for Drug Evaluation and Research, Food and Drug Administra-
tion, USA; Andrew Stone, Alan Barge, AstraZeneca, United
Kingdom; Orhan Suleiman, Centre for Drug Evaluation and Re-
search, Food and Drug Administration, USA; Daniel C. Sullivan,
Duke University Medical Centre, USA; Masakazu Toi, Kyoto
University, Japan; Cindy Welsh, Centre for Drug Evaluation
and Research, Food and Drug Administration, USA.
Finally, the RECIST Working Group would like to thank indi-
vidualswho were not permanent members of the group (which
are all acknowledged as co-authors) but who attended working
group meetings from time to time and made contributions to
the total process over the past 7 years: Richard Pazdur, Food
and Drug Administration, USA; Francesco Pignatti, European
Medicines Agency, London, UK.
Appendix II.
Speciﬁcations for standard
anatomical radiological imaging
These protocols for image acquisition of computed tomogra-
phy (CT) and magnetic resonance imaging (MRI) are recom-
mendations intended for patients on clinical trials where
RECIST assessment will be performed. Standardisation of
imaging requirements and image acquisition parameters is
ideal to allow for optimal comparability of subjects within a
study and results between studies. These recommendations
are designed to balance optimised image acquisition proto-
cols with techniques that should be feasible to perform glob-
ally at imaging facilities in all types of radiology practices.
These guidelines are not applicable to functional imaging
techniques or volumetric assessment of tumour size.
Scanner quality control is highly recommended and should
follow
standard
manufacturer
and
facility
maintenance
schedules using commercial phantoms. It is likely that for RE-
CIST unidimensional measurements this will be adequate to
produce reproducible measurements. Imaging quality control
for CT includes an analysis of image noise and uniformity and
CT number as well as spatial resolution. The frequency of
quality control analysis is also variable and should focus on
clinically relevant scanning parameters. Dose analysis is al-
ways important and the use of imaging should follow the
ALARA principle, ‘As Low As Reasonably Achievable’, which
refers to making every reasonable effort to maintain radiation
exposures as far below the dose limits as possible.
Speciﬁc.notes
Chest X-ray measurement of lesions surrounded by pulmon-
ary
parenchyma
is
feasible,
but
not
preferable
as
the
measurement represents a summation of densities. Further-
more, there is poor identiﬁcation of new lesions within the
chest on X-ray as compared with CT. Therefore, measure-
ments of pulmonary parenchymal lesions as well as medias-
tinal disease are optimally performed with CT of the chest.
MRI of the chest should only be performed in extenuating cir-
cumstances. Even if IV contrast cannot be administered (for
example, in the situation of allergy to contrast), a non-con-
trast CT of the chest is still preferred over MRI or chest X-ray.
CT scans: CT scans of the chest, abdomen, and pelvis should
be contiguous throughout all the anatomic region of interest.
As a general rule, the minimum size of a measurable lesion at
baseline should be no less than double the slice thickness and
also have a minimum size of 10 mm (see below for minimum
size when scanners have a slice thickness more than 5 mm).
While the precise physics of lesion size and partial volume
averaging is complex, lesions smaller than 10 mm may be dif-
ﬁcult to accurately and reproducibly measure. While this rule
is applicable to baseline scans, as lesions potentially decrease
in size at follow-up CT studies, they should still be measured.
Lesions which are reported as ‘too small to measure’ should
be assigned a default measurement of 5 mm if they are still
visible.
The most critical CT image acquisition parameters for opti-
mal tumour evaluation using RECIST are anatomic coverage,
contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most
solid tumours is the chest, abdomen and pelvis. Cover-
age should encompass all areas of known predilection
for metastases in the disease under evaluation and
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should additionally investigate areas that may be
involved based on signs and symptoms of individual
patients. Because a lesion later identiﬁed in a body part
not scanned at baseline would be considered as a new
lesion representing disease progression, careful consid-
eration should begiven to the extent of imaging coverage
at baseline and at subsequent follow-up time points.
This will enable better consistency not only of tumour
measurements but also identiﬁcation of new disease.
b. IV contrast administration: Optimal visualisation and
measurement of metastases in solid tumours requires
consistent administration (dose and rate) of IV contrast
as well as timing of scanning. Typically, most abdomi-
nal imaging is performed during the portal venous
phase and (optimally) about the same time frame after
injection on each examination (see Fig. 1 for impact of
different phase of IV contrast on lesion measurement).
Most solid tumours may be scanned with a single
phase after administration of contrast. While triphasic
CT scans are sometimes performed on other types of
vascular tumours to improve lesion conspicuity, for
consistency and uniformity, we would recommend tri-
phasic
CT
for
hepatocellular
and
neuroendocrine
tumours for which this scanning protocol is generally
standard of care, and the improved temporal resolution
of the triphasic scan will enhance the radiologists’ abil-
ity to consistently and reproducibly measure these
lesions. The precise dose and rate of IV contrast is
dependent upon the CT scanning equipment, CT acqui-
sition protocol, the type of contrast used, the available
venous
access
and
the
medical
condition
of
the
patient. Therefore, the method of administration of
intravenous contrast agents is variable. Rather than
try to institute rigid rules regarding methods for
administering contrast agents and the volume injected,
it is appropriate to suggest that an adequate volume of
a suitable contrast agent should be given so that the
metastases are demonstrated to best effect and a con-
sistent method is used on subsequent examinations for
any given patient (ideally, this would be speciﬁed in
the protocol or for an institution). It is very important
that the same technique be used at baseline and on fol-
low-up examinations for a given patient. This will
greatly enhance the reproducibility of the tumour mea-
surements. If prior to enrolment it is known a patient is
not able to undergo CT scans with IV contrast due to
allergy
or
renal
insufﬁciency,
the
decision
as
to
whether a non-contrast CT or MRI (with or without IV
contrast) should be used to evaluate the subject at
baseline and follow-up should be guided by the tumour
type under investigation and the anatomic location of
the disease. For patients who develop contraindica-
tions to contrast after baseline contrast CT is done,
the decision as to whether non-contrast CT or MRI
(enhanced or non-enhanced) should be performed
should also be based on the tumour type, anatomic
location of the disease and should be optimised to
allow for comparison to the prior studies if possible.
Each case should be discussed with the radiologist to
determine if substitution of these other approaches is
possible and, if not, the patient should be considered
not evaluable from that point forward. Care must be
taken in measurement of target lesions on a different
modality and interpretation of non-target disease or
new lesions, since the same lesion may appear to have
a different size using a new modality (see Fig. 2 for a
comparison of CT and MRI of the same lesion). Oral
contrast is recommended to help visualise and differ-
entiate structures in the abdomen.
c. Slice thickness and reconstruction interval: RECIST measure-
ments may be performed at most clinically obtained
slice thicknesses. It is recommended that CT scans be
performed at 5 mm contiguous slice thickness or less
and indeed this guideline presumes a minimum 5 mm
thickness in recommendations for measurable lesion
deﬁnition. Indeed, variations in slice thickness can have
an impact on lesion measurement and on detection of
new lesions. However, consideration should also be
given for minimising radiation exposure. With these
parameters, a minimum 10 mm lesion is considered
measurable at baseline. Occasionally, institutions may
perform medically acceptable scans at slice thicknesses
greater than 5 mm. If this occurs, the minimum size of
measurable lesions at baseline should be twice the slice
Fig. 1 – Difference in measurement/visualisation with different phases of IV contrast administration. Hypervascular
metastases imaged in the arterial phase (left) and the portal venous phase (right). Note that the number of lesions visible
differs greatly between the two phases of contrast administration as does any potential lesion measurement. Consistent CT
scan acquisition, including phase of contrast administration, is important for optimal and reproducible tumour
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241


thickness of the baseline scans. Most contemporary CT
scanners are multidetector which have many imaging
options for these acquisition parameters.23 The equip-
ment vendor and scanning manual should be reviewed
if there are any speciﬁc system questions.
d. Alternative contrast agents: There are a number of other,
new contrast agents, some organ speciﬁc.24 They may
be used as part of patient care for instance, in liver
lesion assessment, or lymph node characterisation25,
but should not as yet be used in clinical trials.
FDG-PET has gained acceptance as a valuable tool for
detecting, staging and restaging several malignancies. Criteria
for incorporating (or substituting) FDG-PET into anatomical
assessment of tumour response in phase II trials are not yet
available, though much research is ongoing. Nevertheless,
FDG-PET is being used in many drug development trials both
as a tool to assess therapeutic efﬁcacy and also in assessment
of progression. If FDG-PET scans are included in a protocol, by
consensus, an FDG uptake period of 60 min prior to imaging
has been decided as the most appropriate for imaging of pa-
tients with malignancy.26 Whole-body acquisition is impor-
tant since this allows for sampling of all areas of interest
and can assess if new lesions have appeared thus determining
the possibility of interval progression of disease. Images from
the base of the skull to the level of the mid-thigh should be ob-
tained 60 min post injection. PET camera speciﬁcations are
variable and manufacturer speciﬁc, so every attempt should
be made to use the same scanner, or the same model scanner,
for serial scans on the same patient. Whole-body acquisitions
can be performed in either 2- or 3-dimensional mode with
attenuation correction, but the method chosen should be con-
sistent across all patients and serial scans in the clinical trial.
PET/CT scans: Combined modality scanning such as with
PET–CT is increasingly used in clinical care, and is a modal-
ity/technology that is in rapid evolution; therefore, the recom-
mendations in this paper may change rather quickly with
time. At present, low dose or attenuation correction CT por-
tions of a combined PET–CT are of limited use in anatomically
based efﬁcacy assessments and it is therefore suggested that
they should not be substituted for dedicated diagnostic con-
trast enhanced CT scans for anatomically based RECIST mea-
surements. However, if a site can document that the CT
performed as part of a PET–CT is of identical diagnostic qual-
ity to a diagnostic CT (with IV and oral contrast) then the CT
portion of the PET–CT can be used for RECIST measurements.
Note, however, that the PET portion of the CT introduces addi-
tional data which may bias an investigator if it is not routinely
or serially performed.
Ultrasound examinations should not be used in clinical trials
to measure tumour regression or progression of lesions be-
cause the examination is necessarily subjective and operator
dependent. The reasons for this are several: Entire examina-
tions cannot be reproduced for independent review at a later
date, and it must be assumed, whether or not it is the case,
that the hard-copy ﬁlms available represent a true and accu-
rate reﬂection of events. Furthermore, if, for example, the
only measurable lesion is in the para-aortic region of the
abdomen and if gas in the bowel overlies the lesion, the lesion
will not be detected because the ultrasound beam cannot
penetrate the gas. Accordingly, the disease staging (or restag-
ing for treatment evaluation) for this patient will not be
accurate.
While evaluation of lesions by physical examination is also
of limited reproducibility, it is permitted when lesions are
superﬁcial, at least 10 mm size, and can be assessed using
calipers. In general, it is preferred if patients on clinical trials
have at least one lesion that is measurable by CT. Other skin
or palpable lesions may be measured on physical examina-
tion and be considered target lesions.
Use of MRI remains a complex issue. MRI has excellent
contrast, spatial and temporal resolution; however, there
are many image acquisition variables involved in MRI, which
greatly impact image quality, lesion conspicuity and mea-
surement. Furthermore, the availability of MRI is variable
globally. As with CT, if an MRI is performed, the technical
speciﬁcations of the scanning sequences used should be
optimised for the evaluation of the type and site of disease.
Furthermore, as with CT, the modality used at follow-up
should be the same as was used at baseline and the lesions
should be measured/assessed on the same pulse sequence.
Generally, axial imaging of the abdomen and pelvis with T1
and T2 weighted imaging along with gadolinium enhanced
imaging should be performed. The ﬁeld of view, matrix,
number of excitations, phase encode steps, use of fat sup-
pression and fast sequences should be optimised for the spe-
Fig. 2 – CT versus MRI of same lesions showing apparent ‘progression’ due only to differing method of measurement.
242
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ciﬁc body part being imaged as well as the scanner utilised. It
is beyond the scope of this document or appendix to pre-
scribe speciﬁc MRI pulse sequence parameters for all scan-
ners, body parts and diseases. Ideally, the same type of
scanner should be used and the image acquisition protocol
should be followed as closely as possible to prior scans. Body
scans should be performed with breath-hold scanning tech-
niques if possible.
Selection of target lesions: In general, the largest lesions rep-
resentative of involved organs (up to a maximum of two per
organ and ﬁve total) are selected to follow as target lesions.
However, in some cases, the largest lesions may not be easily
measured and are not suitable for follow-up because of their
conﬁguration. In these cases, identiﬁcation of the largest most
reproducible lesions is advised. Fig. 3 provides an illustrative
example where the largest lesion is not the most reproducible
and another lesion is better to select and follow:
Measurement of lesions
The longest diameter of selected lesions should be measured
in the plane in which the images were acquired. For body CT,
this is the axial plane. In the event isotropic reconstructions
are performed, measurements can be made on these recon-
structed images; however, it should be cautioned that not
all radiology sites are capable of producing isotropic recon-
structions. This could lead to the undesirable situation of
measurements in the axial plane at one assessment point
and in a different plane at a subsequent assessment. There
are some tumours, for instance paraspinal lesions, which
are better measured in the coronal or sagittal plane. It would
be acceptable to measure these lesions in these planes if the
reconstructions in those planes were isotropic or the images
were acquired with MRI in those planes. Using the same plane
of evaluation, the maximal diameter of each target lesion
should always be measured at subsequent follow-up time
points even if this results in measuring the lesion at a differ-
ent slice level or in a different orientation or vector compared
with the baseline study. Software tools that calculate the
maximal diameter for a perimeter of a tumour may be em-
ployed and may even reduce variability.
The only exception to the longest diameter rule is lymph
node measurement. Because malignant nodes are identiﬁed
by the length of their short axis, this is the guide used to
determine not only whether they are pathological but is also
the dimension measured for adding into the sum of target le-
sions. Fig. 4 illustrates this point: the large arrow identiﬁes a
malignant node: the shorter perpendicular axis is P15 mm
and will be recorded. Close by (small arrow) there is a normal
node: note here the long axis is greater than 10 mm but the
short axis is well below 10 mm. This node should be consid-
ered non-pathological.
If a lesion disappears and reappears at a subsequent time
point it should continue to be measured. However, the pa-
tient’s response at the point in time when the lesion reap-
pears will depend upon the status of his/her other lesions.
For example, if the patient’s tumour had reached a CR status
and the lesion reappeared, then the patient would be consid-
ered PD at the time of reappearance. In contrast, if the tumour
status was a PR or SD and one lesion which had disappeared
then reappears, its maximal diameter should be added to the
sum of the remaining lesions for a calculated response: in
other words, the reappearance of an apparently ‘disappeared’
single lesion amongst many which remain is not in itself en-
Fig. 3 – Largest lesion may not be most reproducible: most reproducible should be selected as target. In this example, the
primary gastric lesion (circled at baseline and at follow-up in the top two images) may be able to be measured with thin
section volumetric CT with the same degree of gastric distention at baseline and follow-up. However, this is potentially
challenging to reproduce in a multicentre trial and if attempted should be done with careful imaging input and analysis. The
most reproducible lesion is a lymph node (circled at baseline and at follow-up in the bottom two images).
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243


ough to qualify for PD: that requires the sum of all lesions to
meet the PD criteria. The rationale for such a categorisation is
based upon the realisation that most lesions do not actually
‘disappear’ but are not visualised because they are beyond
the resolving power of the imaging modality employed.
The identiﬁcation of the precise boundary deﬁnition of a
lesion may be difﬁcult especially when the lesion is embed-
ded in an organ with a similar contrast such as the liver, pan-
creas, kidney, adrenal or spleen. Additionally, peritumoural
oedema may surround a lesion and may be difﬁcult to distin-
guish on certain modalities between this oedema and actual
tumour. In fact, pathologically, the presence of tumour cells
within the oedema region is variable. Therefore, it is most
critical that the measurements be obtained in a reproducible
manner from baseline and all subsequent follow-up time-
points. This is also a strong reason to consistently utilise
the same imaging modality.
When lesions ‘fragment’, the individual lesion diameters
should be added together to calculate the target lesion
sum. Similarly, as lesions coalesce, a plane between them
may be maintained that would aid in obtaining maximal
diameter measurements of each individual lesion. If the le-
sions have truly coalesced such that they are no longer sep-
arable, the vector of the longest diameter in this instance
should be the maximal longest diameter for the ‘merged
lesion’.
Progression of non-target lesions
To achieve ‘unequivocal progression’ there must be an overall
level of substantial worsening in non-target disease that is of
a magnitude that, even in the presence of SD or PR in target
disease, the treating physician would feel it important to
change therapy. Examples of unequivocal progression are
shown in Figs. 5 and 6.
Fig. 5 – Example of unequivocal progression in non-target lesions in liver.
Fig. 6 – Example of unequivocal progression in non-target lesion (nodes).
Fig. 4 – Lymph node assessment: large arrow illustrates a
pathological node with the short axis shown as a solid line
which should be measured and followed. Small arrow illus-
trates a non-pathological node which has a short axis
<10 mm.
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Appendix III. Frequently asked questions
Question
Answer
What should be done if several unique lesions at
baseline become conﬂuent at a follow-up
evaluation?
Measure the longest diameter of the conﬂuent mass and record to add into the sum of
the longest diameters
How large does a new lesion have to be to count
as progression? Does any small subcentimetre
lesion qualify, or should the lesion be at least
measurable?
New lesions do not need to meet ‘measurability criteria’ to be considered valid. If it is
clear on previous images (with the same technique) that a lesion was absent then its
deﬁnitive appearance implies progression. If there is any doubt (because of the
techniques or conditions) then it is suggested that treatment continue until next
scheduled assessment when, generally, all should be clear. Either it gets bigger and the
date of progression is the date of the ﬁrst suspicion, or it disappears and one may then
consider it an artefact with the support of the radiologists
How should one lesion be measured if on
subsequent exams it is split into two?
Measure the longest diameter of each lesion and add this into the sum
Does the deﬁnition of progression depend on
the status of all target lesions or only one?
As per the RECIST 1.1 guideline, progression requires a 20% increase in the sum of
diameters of all target lesions AND a minimum absolute increase of 5 mm in the sum
Are RECIST criteria accepted by regulatory
agencies?
Many cooperative groups and members of pharma were involved in preparing RECIST
1.0 and have adopted them. The FDA was consulted in their development and supports
their use, though they don’t require it. The European and Canadian regulatory
authorities also participated and the RECIST criteria are now integrated in the European
note for guidance for the development of anticancer agents. Many pharmaceutical
companies are also using them. RECIST 1.1 was similarly widely distributed before
publication
What is the criterion for a measurable lesion if
the CT slice thickness is >5 mm?
RECIST 1.1 recommends that CT scans have a maximum slice thickness of 5 mm and the
minimum size for a measurable lesion is twice that: 10 mm (even if slice thickness is
<5 mm). If scanners with slice thickness >5 mm are used, the minimum lesion size must
have a longest diameter twice the actual slice thickness
What should we record when target lesions
become so small they are below the 10 mm
‘measurable’ size?
Target lesion measurability is deﬁned at baseline. Thereafter, actual measurements,
even if <10 mm, should be recorded. If lesions become very small, some radiologists
indicate they are ‘too small to measure’. This guideline advises that when this occurs, if
the lesion is actually still present, a default measurement of 5 mm should be applied. If
in fact the radiologist believes the lesion has gone, a default measurement of 0 mm
should be recorded
If a patient has several lesions which have
decreased in size to meet PR criteria and one
has actually disappeared, does that patient have
PD if the ‘disappeared’ lesion reappears?
Unless the sum meets the PD criteria, the reappearance of a lesion in the setting of PR (or
SD) is not PD. The lesion should simply be added into the sum.
If the patients had had a CR, clearly reappearance of an absent lesion would qualify for
PD
When measuring the longest diameter of target
lesions in response to treatment, is the same
axis that was used initially used subsequently,
even if there is a shape change to the lesion that
may have produced a new longest diameter?
The longest diameter of the lesion should always be measured even if the actual axis is
different from the one used to measure the lesion initially (or at different time point
during follow-up)
The only exception to this is lymph nodes: as per RECIST 1.1 the short axis should
always be followed and as in the case of target lesions, the vector of the short axis may
change on follow-up
Target lesions have been selected at baseline
and followed but then one of these target
lesions then becomes non-evaluable (i.e.
different technique used)
What may be done in such cases is one of the following:
What is the effect this has on the other target
lesions and the overall response?
(a) If the patient is still being treated, call the centre to be sure that future evaluations are
done with the baseline technique so at least SOME courses are fully evaluable
(b) If that is not possible, check if there IS a baseline exam by the same technique which
was used to follow patients...in which case if you retrieve the baseline measures from
that technique you retrieve the lesion evaluability
(c) If neither (a) nor (b) is possible then it is a judgement call about whether you delete
the lesion from all forms or consider the impact of the lesion overall is so important that
its being non-evaluable makes the overall response interpretation inevaluable without
it. Such a decision should be discussed in a review panel
It is NOT recommended that the lesion be included in baseline sums and then excluded
from follow-up sums since this biases in favour of a response
(continued on next page)
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Appendix III – continued
Question
Answer
What if a single non-target lesion cannot be reviewed, for
whatever reason; does this negate the overall assessment?
Sometimes the major contribution of a single non-target lesion may be in
the setting of CR having otherwise been achieved: failure to examine one
non-target in that setting will leave you unable to claim CR. It is also
possible that the non-target lesion has undergone such substantial
progression that it would override the target disease and render patient
PD. However, this is very unlikely, especially if the rest of the measurable
disease is stable or responding
A patient has a 32% decrease in sum cycle 2, a 28% decrease cycle
4 and a 33% decrease cycle 6. Does conﬁrmation of PR have to
take place in sequential scans or is a case like this conﬁrmed PR?
It is not infrequent that tumour shrinkage hovers around the 30% mark.
In this case, most would consider PR to have been conﬁrmed looking at
this overall case. Had there been two or three non-PR observations
between the two time point PR responses, the most conservative
approach would be to consider this case SD
In the setting of a breast cancer neoadjuvant study, would
mammography not be used to assess lesions? Is CT preferred in
this setting?
Neither CT nor mammography are optimal in this setting. MRI is the
preferred modality to follow breast lesions in a neoadjuvant setting
A patient has a lesion measurable by clinical exam and by CT
scan. Which should be followed?
CT scan. Always follow by imaging if that option exists since it can be
reviewed and veriﬁed
A lesion which was solid at baseline has become necrotic in the
centre. How should this be measured?
The longest diameter of the entire lesion should be followed. Eventually,
necrotic lesions which are responding to treatment decrease in size. In
reporting the results of trials, you may wish to report on this
phenomenon if it is seen frequently since some agents (e.g. angiogenesis
inhibitors) may produce this effect
If I am going to use MRI to follow disease, what is minimum size
for measurability?
MRI may be substituted for contrast enhanced CT for some sites, but not
lung. The minimum size for measurability is the same as for CT (10 mm)
as long as the scans are performed with slice thickness of 5 mm and no
gap. In the event the MRI is performed with thicker slices, the size of a
measurable lesion at baseline should be two times the slice thickness. In
the event there are inter-slice gaps, this also needs to be considered in
determining the size of measurable lesions at baseline
Can PET–CT be used with RECIST?
At present, the low dose or attenuation correction CT portion of a
combined PET–CT is not always of optimal diagnostic CT quality for use
with RECIST measurements. However, if your site has documented that
the CT performed as part of a PET–CT is of the same diagnostic quality as
a diagnostic CT (with IV and oral contrast) then the PET–CT can be used
for RECIST measurements. Note, however, that the PET portion of the CT
introduces additional data which may bias an investigator if it is not
routinely or serially performed
246
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13. Macdonald DR, Cascino TL, Schold Jr SC, Cairncross JG.
Response criteria for phase II studies of supratentorial
malignant glioma. J Clin Oncol 1990;8:1277–80.
14. Cheson BD, Pﬁstner B, Juweid ME, et al. Revised response
criteria for malignant lymphoma. J Clin Oncol 2007;10:579–86.
15. Schwartz LH, Bogaerts J, Ford R, et al. Evaluation of lymph
nodes with RECIST 1.1. Eur J Cancer 2009;45:261–7.
16. Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to
evaluate the response to treatment in solid tumors (ovarian
cancer). J Natl Cancer Inst 2004;96:487–8.
17. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response
guidelines for phase II clinical trials in androgen-independent
prostate cancer: recommendations from the Prostate-Speciﬁc
Antigen Working Group. J Clin Oncol 1999;17:3461–7.
18. Scher H, Halabi S, Tannock I, et al. Design and end points of
clinical trials for patients with progressive prostate cancer
and castrate levels of testosterone: recommendations of the
Prostate Cancer Clinical Trials Working Group. J Clin Oncol
2008;26:1148–59.
19. Vergote I, Rustin GJ, Eisenhauer EA, et al. Re: new guidelines
to evaluate the response to treatment in solid tumors [ovarian
cancer]. Gynecologic Cancer Intergroup. J Natl Cancer Inst
2000;92:1534–5.
20. Van Glabbeke M, Verweij J, Judson I, Nielsen OS. EORTC Soft
Tissue and Bone Sarcoma Group: Progression-free rate as the
principal end-point for phase II trials in soft-tissue sarcomas.
Eur J Cancer 2002;38:543–9.
21. Dancey JE, Dodd LE, Ford R, et al. Recommendations for the
assessment of progression in randomised cancer treatment
trials. Eur J Cancer 2009;45:281–9.
22. Ford R, Schwartz L, Dancey J, et al. Lessons learned
from independent central review. Eur J Cancer 2009;45:
268–74.
23. Catalano C, Francone M, Ascarelli A, Mangia M, Iacucci I,
Passariello R. Optimizing radiation dose and image quality.
Eur Radiol 2007;17(Suppl 6):F26–32.
24. Low RN. Abdominal MRI advances in the detection of liver
tumours and characterization. Lancet Oncol 2007;8(6):525–35.
25. Barrett T, Choyke PL, Kobayashi H. Imaging of the lymphatic
system: new horizons. Contrast Media Mol Imaging
2006;1(6):230–45.
26. Shankar LK, Hoffman JM, Bacharach S, et al. National
Cancer Institute. Consensus recommendations for the use
of 18F-FDG PET as an indicator of therapeutic response
in patients in National Cancer Institute Trials.
J Nucl Med 2006;47(6):1059–66.
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Protocol CF102-201HCC, Amendment 5 
Confidential 
6 November 2018 
 
91 
APPENDIX B: 
PERFORMANCE STATUS AND CARDIAC FUNCTION SCALES 
Level 
ECOG Performance Status* 
0 
Normal activity 
1 
Symptoms but ambulatory 
2 
In bed < 50% of time 
3 
In bed > 50 % of time 
4 
100 % bedridden 
* 
Oken, 1982 
 
Cardiac Functional Classification 
NYHA Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g., 
shortness of breath when walking, climbing stairs, etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, 
e.g., walking short distances (20–100 m). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound 
patients. 
The Criteria Committee of the NYHA, 1994 
 
 


Can-Fite BioPharma, Ltd. 
Protocol CF102-201HCC, Amendment 5 
Confidential 
6 November 2018 
 
92 
APPENDIX C: CHILD-PUGH CLASSIFICATION OF SEVERITY OF LIVER 
DISEASE 
Child-Pugh classification of severity of liver disease according to the degree of ascites, plasma 
concentrations of bilirubin and albumin, prothrombin time, and the degree of encephalopathy. 
Class A (well-compensated disease): total score of 5-6. 
Class B (significant functional compromise): total score of 7-9. 
Class C (decompensated disease): total score of 10-15. 
These classes correlate with 1- and 2-year patient survival. 
Parameter 
Points Assigned 
1 
2 
3 
Ascites 
Absent 
Slight 
Moderate 
Bilirubin, mg/dL 
<2 
2-3 
>3 
Albumin, g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time 
* Seconds over control 
* INR 
 
1-3 
<1.7 
 
4-6 
1.7-2.3 
 
>6 
>2.3 
Encephalopathy 
None 
Grade 1-2 
Grade 3-4 
Child, 1964; Pugh, 1973 
 
 


Can-Fite BioPharma, Ltd. 
Protocol CF102-201HCC, Amendment 5 
Confidential 
6 November 2018 
 
93 
APPENDIX D: CLINICAL LABORATORY TESTS 
Except for the “OTHER” category, the following laboratory tests will be performed at Pre-Study Visit; 
Days 1 (i.e., the Baseline Visit if not performed ≤ 3 days prior), 8, and 15 of Cycle 1; Days 1 and 15 of 
subsequent cycles; EOS; and Follow-Up. 
HEMATOLOGY TESTS 
CHEMISTRY TESTS 
• 
hematocrit 
• 
hemoglobin 
• 
platelet count 
• 
red blood cell count 
• 
white blood cell count and differential 
(absolute and percentage); neutrophils, 
lymphocytes, monocytes, eosinophils, 
basophils, and reticulocyte count 
 
• 
alanine aminotransferase (ALT) 
• 
albumin 
• 
alkaline phosphatase 
• 
aspartate aminotransferase (AST) 
• 
bicarbonate 
• 
bilirubin (direct and total) 
• 
blood urea nitrogen (BUN) 
• 
calcium 
• 
chloride 
• 
creatinine 
• 
glucose 
• 
lactate dehydrogenase (LDH) 
• 
phosphorus 
• 
potassium 
• 
sodium 
• 
total protein 
• 
uric acid 
URINALYSIS 
• 
glucose 
• 
ketones 
• 
occult blood 
• 
pH 
• 
protein 
• 
specific gravity 
• 
and, when indicated by dipstick abnormality, 
microscopic sediment evaluation 
 
COAGULATION PARAMETERS 
OTHER 
• 
International Normalized Ratio (INR) 
• 
partial thromboplastin time (PTT) 
• 
prothrombin time (PT) 
• 
alpha-fetoprotein (AFP): at baseline and Day 1 
of each subsequent cycle  
• 
thyroid functions (T3, T4, TSH) at Pre-Study, 
Baseline, Day 1 of subsequent cycles, EOS, 
and Follow-up 
• 
serum pregnancy test: females of childbearing 
potential 
• 
hepatitis B and C viral load measurement every 
odd numbered cycle (where applicable) 
 
 


Can-Fite BioPharma, Ltd. 
Protocol CF102-201HCC, Amendment 5 
Confidential 
6 November 2018 
 
94 
APPENDIX E: 
ALGORITHM FOR THE DIAGNOSIS OF HCC IN PATIENTS WITH 
UNDERLYING CIRRHOSIS1 
 
 
                                                 
1 American Association for the Study of Liver Diseases Practice Guideline (Bruix, 2005) 

SAP_001.pdf: 
Can-Fite BioPharma, Ltd. 
CF102-201HCC  
Statistical Analysis Plan 
 
Page 1 of 39 
 
 
A Phase 2, Randomized, Double-Blind, Placebo- Controlled 
Study of the Efficacy and Safety of CF102 in the Second-
Line Treatment of Advanced Hepatocellular Carcinoma in 
Subjects with Child-Pugh Class B Cirrhosis 
 
STATISTICAL ANALYSIS PLAN 
Version 7.0 
 29 August 2019 
 
CONFIDENTIAL 
 
Submitted to: 
 
Motti Farbstein 
Chief Operating Officer 
 
Pnina Fishman, PhD 
Chief Executive Officer 
Can-Fite BioPharma, Ltd 
10 Bareket St. 
Kiryat Matalon, Petach Tikva 49170 
Israel 
 
Michael H Silverman, MD 
BioStrategics Consulting, Ltd  
Marblehead, MA 01945 USA 
 
Prepared by: 
David R. Bristol, PhD 
Statistical Consulting Services Inc. 
2075 Denise Lane 
Winston-Salem, North Carolina 27127 USA 
 
 


Can-Fite BioPharma, Ltd. 
CF102-201HCC  
Statistical Analysis Plan 
 
Page 2 of 39 
 
  
 
SIGNATURE PAGE 
 
Prepared by: 
 
 
 
______________________________________ 
________________ 
David Bristol, PhD 
 
 
 
 
 
Date 
Statistical Consulting Services, Inc. 
 
 
 
 
Approved by: 
 
 
 
______________________________________ 
________________ 
Michael H. Silverman , MD  
 
 
 
Date 
BioStrategics Consulting, Ltd. 
 
 
 
______________________________________ 
________________ 
Motti Farbstein 
 
 
 
 
 
Date 
Chief Operating Officer 
Can-Fite BioPharma, Ltd. 
 
 
 
______________________________________ 
________________ 
Pnina Fishman, PhD  
 
 
 
 
 Date 
Chief Executive Officer  
Can-Fite BioPharma, Ltd. 


Can-Fite BioPharma, Ltd. 
CF102-201HCC  
Statistical Analysis Plan 
 
Page 3 of 39 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
A3AR  
Adenosine A3 receptor (A3AR) 
AASLD 
American Association for the Study of Liver Diseases 
AE(s) 
Adverse event(s) 
AFP 
α-fetoprotein (alpha-fetoprotein) 
ALT 
Alanine Aminotransferase (also referred to as SGPT, ALAT) 
ANC  
Absolute neutrophil count 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase (also referred to as SGOT, ASAT) 
BID 
Twice a day 
BMI 
Body mass index 
BUN 
Blood Urea Nitrogen 
CBC 
Complete blood count 
CF102 
Sponsor defined name for the study medication 
CFB 
Change From Baseline 
cm 
Centimeter(s)  
CP 
Child-Pugh  
CPB 
Child-Pugh Class B (cirrhosis) 
CR  
Complete Response 
CRF 
Case Report Form 
CS 
Clinically Significant 
CT 
Computed Tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
DB 
Double Blind 
DC 
Disease Control (CR + PR + SD) 
DCR 
Disease Control (CR + PR + SD) Rate; also referred to as DC Rate 
ECG 
Electrocardiogram 
ECOG  
Eastern Collaborative Oncology Group  
EHS 
Extrahepatic Spread 
EOS  
End Of Study (end of dosing) 
HBV 
Hepatitis B Virus 
HCC  
Hepatocellular carcinoma 
HCV  
Hepatitis C Virus  
HR  
Heart rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ID 
Identification 
IMP 
Investigational medicinal product 
INR  
International normalized ratio 
ITT 
Intent-to-treat 
kg 
Kilogram(s) 
KM 
Kaplan-Meier 
LD  
Longest diameter 
LDH 
Lactate dehydrogenase 


Can-Fite BioPharma, Ltd. 
CF102-201HCC  
Statistical Analysis Plan 
 
Page 4 of 39 
 
Abbreviation 
Definition 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
mmHg 
Millimeter of Mercury 
MRI  
Magnetic resonance imaging 
NAB 
Normal Approximation to the Binomial Distribution 
NCI 
National Cancer Institute 
NCS 
Not clinically significant 
NYHA 
New York Heart Association 
OL 
Open Label  
OR 
Objective response (CR + PR) 
ORR 
Objective response (CR + PR) Rate; also referred to as OR Rate 
OS 
Overall Survival 
PBMC  
Peripheral blood mononuclear cells 
PD  
Progressive disease 
PE 
Physical examination 
PFS 
Progression-Free Survival 
PK  
Pharmacokinetic(s) 
PO 
per os; oral(ly) 
PR  
Partial response 
PS  
Performance status 
PT 
Prothrombin Time (laboratory parameter);  
Preferred Term (MedDRA) 
PTT 
Partial Thromboplastin Time 
PVT 
Portal Vein Thrombosis 
QTc 
Corrected QT  
QTcF 
Corrected QT (Fridericia) 
RECIST  
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD  
Stable disease (also Standard Deviation in tables) 
SE 
Standard Error 
SGOT 
Serum Glutamic Oxaloacetic Transaminase (also referred to as AST) 
SGPT 
Serum Glutamic Pyruvic Transaminase (also referred to as ALT) 
SOC 
System Organ Class (MedDRA) 
TEAE 
Treatment-emergent adverse event 
TTP 
Time To Progression 
ULN 
Upper limit of normal 
WBC 
White blood cell count 
 
 
 
 
 


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CF102-201HCC  
Statistical Analysis Plan 
 
Page 5 of 39 
 
Section 
TABLE OF CONTENTS 
Page 
1. 
INTRODUCTION AND BACKGROUND ............................................................ 7 
2. 
TRIAL DESIGN........................................................................................................ 7 
2.1 
STUDY OBJECTIVES ............................................................................................. 7 
2.2 
STUDY DESIGN .................................................................................................... 7 
2.3 
STUDY DRUG DOSAGE AND ADMINISTRATION .................................................... 8 
2.4 
DOSE MODIFICATION ........................................................................................... 8 
3. 
SAMPLE SIZE, RANDOMIZATION AND BLINDING ..................................... 9 
3.1 
SAMPLE SIZE ........................................................................................................ 9 
3.2 
RANDOMIZATION AND BLINDING ......................................................................... 9 
4. 
SELECTION AND WITHDRAWAL ..................................................................... 9 
4.1 
INCLUSION CRITERIA ........................................................................................... 9 
4.2 
EXCLUSION CRITERIA ........................................................................................ 10 
4.3 
DISCONTINUATION FROM DOSING ...................................................................... 11 
4.4 
WITHDRAWAL FROM THE TRIAL ........................................................................ 12 
5. 
CLINICAL PROCEDURES AND ASSESSMENTS ........................................... 12 
Table 1–1: 
Schedule of Events for Double Blind (DB) Period ........................... 13 
Table 1–2: 
Schedule of Events for Open Label (OL) Period .............................. 15 
6. 
STUDY ENDPOINTS ............................................................................................. 17 
6.1 
EFFICACY ASSESSMENTS ................................................................................... 17 
6.1.1 Time to Event Endpoints ............................................................................... 17 
6.1.2 Tumor Response ............................................................................................ 18 
6.1.3 Exploratory Efficacy ..................................................................................... 18 
6.2 
SAFETY EVALUATIONS ...................................................................................... 18 
7. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS ....................... 19 
7.1 
ANALYSIS POPULATIONS ................................................................................... 20 
7.2 
GENERAL ANALYSIS .......................................................................................... 20 
7.3 
SUBJECT DISPOSITION ........................................................................................ 20 
7.4 
DEMOGRAPHICS AND MEDICAL HISTORY .......................................................... 21 
7.4.1 Demographics ............................................................................................... 21 
7.4.2 HCC Disease History And Prior Therapies.................................................. 21 
7.4.3 Medical History ............................................................................................ 22 
7.5 
MEDICATION AND TREATMENT ANALYSIS......................................................... 22 
7.5.1 Compliance and Exposure ............................................................................ 22 
7.5.2 Concomitant Medications ............................................................................. 22 
7.6 
EFFICACY ........................................................................................................... 22 
7.6.1 Overall Survival (OS) ................................................................................... 23 
7.6.2 Time to Progression (TTP) ........................................................................... 23 
7.6.3 Progression-Free Survival (PFS) ................................................................. 23 
7.6.4 Tumor Response ............................................................................................ 24 
7.6.5 Biomarkers .................................................................................................... 24 


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CF102-201HCC  
Statistical Analysis Plan 
 
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7.6.6 Chemistry And Coagulation Parameters ...................................................... 25 
7.6.7 Hepatitis Viral Load ..................................................................................... 25 
7.6.8 Subgroup Analyses ........................................................................................ 26 
7.7 
SAFETY ANALYSES ............................................................................................ 27 
7.7.1 Adverse Events .............................................................................................. 27 
7.7.2 Laboratory Tests ........................................................................................... 28 
7.7.3 ECOG Performance Status ........................................................................... 28 
7.7.4 Vital Signs and Weight .................................................................................. 28 
7.7.5 ECG Parameters ........................................................................................... 29 
7.7.6 Physical Examinations .................................................................................. 29 
8. 
MISSING DATA ..................................................................................................... 30 
9. 
DIFFERENCES AND CHANGES FROM THE PROTOCOL ......................... 30 
10. 
APPENDICES ..................................................................................................... 32 
10.1 
APPENDIX A – CHILD-PUGH CLASSIFICATION OF SEVERITY OF LIVER DISEASE 32 
10.2 
APPENDIX B – DETERMINATION OF OVERALL RESPONSE .................................. 33 
10.3 
APPENDIX C – CLINICAL LABORATORY TESTS .................................................. 37 
10.4 
APPENDIX D – ECOG PERFORMANCE STATUS .................................................. 38 
10.5 
APPENDIX E – CARDIAC FUNCTION CLASSIFICATION ........................................ 39 
 
 
 


Can-Fite BioPharma, Ltd. 
CF102-201HCC  
Statistical Analysis Plan 
 
Page 7 of 39 
 
1. INTRODUCTION AND BACKGROUND 
This Statistical Analysis Plan (SAP; Version 7.0) is to be used in conjunction with the 
protocol (Amendment 5, dated 6 November 2018) and the corresponding case report 
forms (CRFs). Table shells and mock listings corresponding to the contents of this 
document will be prepared and included with the final version. This document, with table 
shells and mock listings, will be reviewed prior to unblinding, and revised if necessary. 
The contents of this document were developed prior to unblinding, except as noted. 
 
CF102 is a selective, high affinity agonist for the human adenosine A3 receptor (A3AR) 
and is being developed as a non-cytotoxic agent for the treatment for hepatocellular 
carcinoma (HCC). A3ARs are expressed primarily in normal lung, liver, kidney and heart 
tissues, with very little expression in the brain or in skeletal muscle. A3ARs are over-
expressed by human HCC cells, but not those from healthy donors. A3AR expression is 
also elevated in PBMC isolated from patients with hepatitis C viral (HCV) infections. 
Further details are given in the protocol. 
 
2. TRIAL DESIGN  
2.1 STUDY OBJECTIVES  
The primary objective of this trial is to: 
 
• Evaluate the efficacy of orally administered CF102 25 mg BID as compared to 
placebo, as determined by Overall Survival (OS), when used as second-line 
therapy in subjects with advanced hepatocellular carcinoma (HCC) and Child-
Pugh Class B (CPB) cirrhosis. 
 
The secondary objectives of this trial are to: 
 
• Evaluate other indicators of efficacy of CF102 25 mg BID as compared to 
placebo, including time to progression (TTP), progression-free survival (PFS), 
objective response (OR) rate, and disease control (DC) rate in this population; 
• Explore exposure-response relationships using sparse pharmacokinetic (PK) 
sampling; 
• Characterize the safety profile of CF102 25 mg BID in subjects with advanced 
HCC and CPB cirrhosis; 
• Characterize the effects of CF102 25 mg BID on laboratory parameters associated 
with viral hepatitis, hepatic dysfunction, and cirrhosis; and 
• Explore the relationship between the white blood cell (WBC) adenosine A3 
receptor (A3AR) expression and clinical response. 
 
The planned analyses of PK results will be presented in a separate document. 
2.2 STUDY DESIGN 
This is a multicenter, randomized, double-blind, placebo-controlled clinical trial in 
subjects with advanced HCC and CPB cirrhosis who did not tolerate prior sorafenib 
therapy or experienced disease progression on prior sorafenib therapy. The trial will 
evaluate the efficacy and safety of CF102 25 mg BID as compared to placebo.  


Can-Fite BioPharma, Ltd. 
CF102-201HCC  
Statistical Analysis Plan 
 
Page 8 of 39 
 
 
Tumor imaging will be performed every 8 weeks. Treatment will continue until the 
subject experiences unacceptable drug-related intolerability. Subjects will return for a 
follow-up visit 28 days after completion of the last dose of study drug, and every attempt 
will be made to obtain survival data on all randomized subjects. Subjects who discontinue 
will be followed indefinitely for survival status. Enrollment will continue until 75 deaths 
have been recorded. All randomized subjects will continue to be followed for survival 
status after 75 deaths have been recorded. 
 
Once the requisite number of events has occurred and the blind is broken for analysis of 
the trial results, any surviving subjects who remain on blinded drug will be offered the 
opportunity to continue dosing with open-label CF102 25 mg BID indefinitely, following 
the protocol-specified schedule of events (Table 1-2), referred to below as the Open-
Label (OL) period. The period prior to breaking the blind is referred to as the Double-
Blind (DB) period.  Bottles of study drug dispensed to subjects at the start of each 
treatment cycle during the OL period will contain a sufficient supply of CF102 for one 
cycle (28 days) of continuous dosing.  
2.3  STUDY DRUG DOSAGE AND ADMINISTRATION 
Subjects will be randomly assigned in a 2:1 ratio to treatment with either CF102 25 mg or 
matching placebo. CF102 or placebo will be self-administered orally twice daily (BID) 
on an empty stomach (1 hour before or 2 hours after meals) beginning on Day 1 of the 
trial and thereafter at approximately the same times each day of the 28-day cycle.  
 
During the OL period, CF102 will be administrated in continuous 28-day cycles 
beginning on Day 1 of Cycle 1 of the OL period.  
2.4 DOSE MODIFICATION 
Any safety-related modification of study drug dosing (i.e., dose reduction or interruption 
of scheduled dosing) and the reason for such action must be clearly noted on the Adverse 
Events page of the CRF, and the Medical Monitor informed. 
 
In the case of any Grade 3 toxicity by CTCAE v4.0 judged by the Principal Investigator 
to be at least “possibly” drug-related, the dose of study drug will be interrupted for up to 
7 days. If toxicity does not resolve to Grade ≤ 1 within 7 days, the subject will be 
discontinued from treatment. If toxicity resolves to Grade ≤ 1 within 7 days, dosing will 
be resumed at the decreased dose of 1 capsule per day.  
 
In the case of any Grade 4 toxicity judged by the Principal Investigator to be at least 
“possibly” drug-related, the dose of study drug will be withdrawn permanently. 
 
Only 1 dose reduction will be allowed. If a Grade 3 or 4 toxicity judged by the Principal 
Investigator to be at least “possibly” drug-related occurs upon rechallenge at the reduced 
dose, study drug dosing will be withdrawn permanently.  
 


Can-Fite BioPharma, Ltd. 
CF102-201HCC  
Statistical Analysis Plan 
 
Page 9 of 39 
 
3. SAMPLE SIZE, RANDOMIZATION AND BLINDING 
3.1 SAMPLE SIZE 
Approximately 78 subjects will be enrolled during an accrual period estimated to be 
approximately 102 weeks (24 months) in duration and randomized to either CF102 or 
placebo using a 2:1 randomization. The post-accrual treatment period will continue until 
a total of 75 subjects have died. Assuming a hazard ratio of 0.5, 75 deaths will provide 
80% power for the logrank test at level 0.05 (EAST 6, Cytel, 2014).  
 
3.2 RANDOMIZATION AND BLINDING 
On Day 1, each subject will be randomly assigned to receive either CF102 25 mg BID or 
placebo BID, using a 2:1 randomization. The subject ID number identifies the subject and 
consists of the site number followed by the subject number for that site. The 
randomization number identifies the treatment.  
 
The trial will be double-blind; the subject, Investigator/staff, and Sponsor will not have 
access to or knowledge of any subject’s treatment assignment. Upon completion of the 
DB period, the blind will be broken and all analyses will be performed. Any surviving 
subjects who remain on blinded drug will be offered the opportunity to continue dosing 
with open-label CF102 25 mg BID indefinitely (OL Period). 
 
4. SELECTION AND WITHDRAWAL  
4.1 INCLUSION CRITERIA 
Inclusion Criteria (DB Period) 
Subjects must meet all of the following inclusion criteria to be eligible for the trial: 
1. Males and females at least 18 years of age. 
2. Diagnosis of HCC: 
• For subjects without underlying cirrhosis at the time of diagnosis, diagnosis 
of HCC documented by cytology and/or histology. 
• For subjects with underlying cirrhosis at the time of diagnosis, diagnosis of 
HCC established according to the American Association for the Study of 
Liver Diseases Practice Guideline algorithm (Appendix E of the protocol). 
3. HCC is advanced, i.e., treatment-refractory or metastatic, and no standard 
therapies are expected to be curative. 
4. Receipt of prior sorafenib therapy for at least 3 weeks and withdrawal from 
treatment due either to intolerability or to radiographic evidence of disease 
progression. If treatment was withdrawn due to intolerability manifested as a 
Grade 3 or 4 event by National Cancer Institute Common Toxicity Criteria for 
Adverse Events (CTCAE v4.0), less than 3 weeks of continuous prior 
administration prior to withdrawal is acceptable (see also Exclusion 
Criterion #3). 
5. Prior sorafenib treatment was discontinued for at least 2 weeks prior to the 
Baseline Visit. 


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CF102-201HCC  
Statistical Analysis Plan 
 
Page 10 of 39 
 
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2 
(Appendix D). 
7. Cirrhosis classified as Child-Pugh Class B (Appendix A). 
8. The following laboratory values must be documented ≤ 3 days prior to the 
first dose of study drug: 
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
• Platelet count ≥ 75 × 109/L 
• Serum creatinine ≤ 2.0 mg/dL 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)  
 
 ≤ 5 × the upper limit of normal (ULN) 
• Total bilirubin ≤ 3.0 mg/dL 
• Serum albumin ≥ 2.8 g/dL 
• Prothrombin time (PT) no greater than 6 seconds longer than control. 
9. Life expectancy of ≥ 6 weeks. 
10. For women of childbearing potential, negative serum pregnancy test result. 
11. Provide written informed consent to participate. 
12. Willing to comply with scheduled visits, treatment plans, laboratory assessments, 
and other trial-related procedures. 
 
Inclusion Criteria (OL Period) 
1. The subject signed the ICF for the Open Label treatment. 
2. The subject received double blind treatment with CF102/placebo and is still taking 
the investigational medication when Amendment 5 is approved. 
 
4.2 EXCLUSION CRITERIA  
Subjects meeting any of the following criteria are ineligible for the trial: 
 
1. Receipt of no, or of >1, prior systemic drug therapies for HCC. 
2. Receipt of systemic cancer therapy, immunomodulatory drug therapy, 
immunosuppressive therapy, or corticosteroids > 20 mg/day prednisone or 
equivalent within 14 days prior to the Baseline Visit or concurrently during 
the trial. 
3. Presence of an acute or chronic toxicity of prior chemotherapy that has not 
resolved to ≤ Grade 1, as determined by CTCAE v 4.0. 
4. Locoregional treatment within 4 weeks prior to the Baseline Visit. 
5. Major surgery or radiation therapy within 4 weeks prior to the Baseline Visit. 
6. Use of any investigational agent within 4 weeks prior to the Baseline Visit. 
7. Child-Pugh Class A or C cirrhosis or hepatic encephalopathy. 
8. Occurrence of esophageal or other gastrointestinal hemorrhage requiring 
transfusion within 4 weeks prior to the Baseline Visit. 
9. Uncontrolled or clinically unstable thyroid disease, per judgment of the 
Principal Investigator. 
10. Active bacterial, viral, or fungal infection requiring systemic therapy, or 
operative or radiological intervention. 
11. Known human immunodeficiency virus- or acquired immunodeficiency 
syndrome- related illness. 


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12. Liver transplant. 
13. Active malignancy other than HCC. 
14. Uncontrolled arterial hypertension or congestive heart failure (New 
York Heart Association Classification 3 or 4) (Appendix E). 
15. Angina, myocardial infarction, cerebrovascular accident, coronary/peripheral 
artery bypass graft surgery, transient ischemic attack, or pulmonary embolism 
within 3 months prior to initiation of study drug. 
16. History of or ongoing cardiac dysrhythmias requiring treatment, atrial 
fibrillation of any grade, or persistent prolongation of the QTc (Fridericia) 
interval to >450 msec for males or >470 msec for females. 
17. Pregnant or lactating female. 
18. Women of childbearing potential, unless they agree to use dual contraceptive 
methods which, in the Investigator’s opinion, are effective and adequate for the 
subject’s circumstances while on study drug. 
19. Men who partner with a woman of childbearing potential, unless they agree to 
use effective, dual contraceptive methods (i.e., a condom, with female partner 
using oral, injectable, or barrier method) while on study drug and for 3 months 
afterward. 
20. Any severe, acute, or chronic medical or psychiatric condition, or laboratory 
abnormality that may increase the risk associated with trial participation or 
study drug administration; may interfere with the informed consent process 
and/or with compliance with the requirements of the trial; or may interfere with 
the interpretation of trial results and, in the Investigator’s opinion, would make 
the subject inappropriate for entry into this trial. 
4.3 DISCONTINUATION FROM DOSING 
Discontinuation from dosing means that the EOS visit is to be performed upon 
termination and indefinite monthly survival follow-up will be performed.  
Subjects should be discontinued from dosing for the following reasons: 
 Grade 3 toxicity considered by the Investigator to be at least “possibly” drug-
related that does not resolve to Grade ≤ 1 within 7 days following interruption of 
treatment. 
 Need for > 1 dose reduction. 
 Grade 4 toxicity considered by the Investigator to be at least “possibly” drug-
related. 
 Treatment interruption or delay for more than 14 days after the next scheduled 
dose due to an event unrelated to toxicity (e.g., intercurrent illness, scheduled 
surgery, etc.). 
 Subject withdrawal of consent for trial participation at any time, for any reason, 
and without prejudice. 
 Withdrawal of a subject by the Investigator, at his/her discretion, for any reason 
that the Investigator believes continuation of study drug therapy would not be in 
the subject’s best interest. The reason for the subject’s discontinuation must be 
recorded on the case report form (CRF). 


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 An intercurrent illness which, in the Investigator’s opinion, would prevent 
completion of trial-related evaluations. 
 Pregnancy. 
 Subject noncompliance with trial or follow-up procedures. 
 Termination of the trial by the Sponsor. 
If a subject is withdrawn from treatment, the Investigator will make every effort to 
complete all final evaluations and laboratory tests required by the protocol. The 
reason(s) for discontinuation of dosing must be clearly documented on the CRF. 
Subjects who discontinue from dosing will be followed indefinitely for survival 
status. 
4.4 WITHDRAWAL FROM THE TRIAL 
 
A subject will be considered to be withdrawn from the trial for the following reasons: 
 Withdrawal of consent (in which every effort will be made to follow the 
subject for survival information); 
 Termination of the trial by the Sponsor; 
 
Patient Death; 
 
Other. 
 
5. CLINICAL PROCEDURES AND ASSESSMENTS 
The schedule of clinical procedures and assessments conducted during the study is 
presented in the following table. Further details are given in the protocol. 
 
 


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TABLE 1–1: 
SCHEDULE OF EVENTS FOR DOUBLE BLIND (DB) PERIOD  
 
 
Cycle 1 
Subsequent 
Cycles 
End of Study/ End 
of Dosing (EOS)l 
Follow-Up 
(28 ± 3 Days 
Post- EOS) 
 
Trial Procedures 
Pre-Study 
(-28 days) 
Day 1 
Baseline 
Days 8 and 15 
± 2 days 
Day 1 
± 2 days 
Day 15 
± 2 days 
 
Day 1 + 2 days 
Medical history 
X 
 
 
 
 
 
 
Physical examination 
Xa 
Xa,c 
Xb 
Xb 
Xb 
Xb 
Xa 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Body weight 
X 
Xc 
 
X 
 
X 
X 
Vital signsd  
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory testinge 
X 
Xc 
X 
X 
X 
X 
X 
T3. T4, TSH 
X 
X 
 
X 
 
X 
X 
ECGf 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (serum)g 
X 
Xc 
 
X 
 
X 
X 
ECOG PSg 
X 
Xc 
 
X 
 
X 
 
α-fetoprotein (AFP) 
 
X 
 
X 
 
X 
X 
WBC A3AR sample 
 
X 
 
Xh 
 
 
 
PK samples 
 
Xk 
Xk 
Xk 
 
 
 
Hepatitis B/C virus serology 
X 
 
 
 
 
 
 
Hepatitis B/C viral load (if 
seropositive) 
 
X 
 
Xi 
 
Xi 
 
Tumor imaging for RECIST 
Xj 
 
 
Xj 
 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
Dispense study drug supplies 
 
X 
 
X 
 
 
 
Review treatment compliance 
 
X 
X 
X 
X 
X 
 
 
 
 


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a Complete PE performed at the Pre-Study (and/or the Baseline Visit if performed > 3 days prior to first dose) and End of Study/End 
of Dosing (EOS) visits. 
b Symptom-directed examination. 
c If Pre-Study assessment was performed ≤ 3 days prior to the Baseline Visit, assessments do not need to be repeated prior to 
initiation of dosing. 
d Temperature, pulse, respiration, blood pressure at: Pre-Study; pre-dose at all visits; at 1, 2, 3, 4h (± 5 min), 6 and 8h (± 10 min) 
post-dose on Cycle 1 Day 1; and at Follow-up. 
e See list of parameters in Appendix C. 
f ECG at Pre-Study; pre-dose at all visits; and at 2, 4, and 8h (± 10 min) post-dose on Cycle 1 Day 1; and at Follow-up. 
g Performed at Pre-Study, prior to the first dose, at the end of each cycle, and at Follow-up. 
h Day 1 of odd-numbered cycles, unless waived by the Sponsor (selected sites only). 
i For subjects with measurable viral load at the Baseline Visit; on Day 1 of odd-numbered cycles only and at EOS. 
j CT scan or MRI at Pre-Study, the end of Cycle 2, and at the end of subsequent even-numbered cycles. For trial eligibility 
purposes, a scan performed ≤ 21 days prior to the Pre- Study Visit may be used (allowed time window is of -7/+1 day with 
respect to day 28 of each even numbered cycles; if performed at +1 day after day 28, CT/MRI scan must be performed 
before administration of the morning dose of that day) 
k Sparse sampling on Day 1 of Cycles 1 and 2 only. Pre-dose trough samples on Cycle 1 Days 8 and 15 only. See Table 10-1 of 
the protocol for PK sampling time points.   
l End of Study visit timeframe is of 2 days since the last administered dose of IMP/matching Placebo. 
 
 
 
 


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TABLE 1–2: 
SCHEDULE OF EVENTS FOR OPEN LABEL (OL) PERIOD 
Trial Procedures  
OL Cycle 1 
Subsequent OL Cycle 
OL End of 
Study/End of 
Dosing (EOS) j 
OL Follow-
up (28 ± 3 
Days Post 
EOS) 
Day 1 
Baseline 
Days 8 and 15 
± 2 Days 
Day 1 
± 2 Days 
Day 15 
± 2 Days 
Day 1 
± 2 Days 
Physical examination 
Xb 
Xb 
Xb 
Xb 
Xa 
Xb 
Eligibility criteria for OL 
X  
 
 
 
 
 
Informed consent for OL 
X 
 
 
 
 
 
Body weight 
X 
 
X 
 
X 
X 
Vital signs c 
X 
X 
X 
X 
X 
X 
Clinical laboratory testing d 
X 
X 
X 
X 
X 
X 
T3, T4, TSH 
X 
 
X 
 
X 
X 
ECG e 
X 
X 
X 
X 
X 
X 
Pregnancy test (serum) f 
X 
 
X 
 
X 
X 
ECOG PS f 
X 
 
X 
 
X 
 
α-fetoprotein (AFP) 
X 
 
X 
 
X 
X 
WBC A3AR sample 
X 
 
Xg 
 
 
 
Hepatitis B/C viral load (if seropositive) 
X 
 
X h 
 
X h 
 
Tumor imaging for RECIST 
 
 
X i 
 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Dispense study drug supplies 
X 
 
X 
 
 
 
Review treatment compliance 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
a. Complete PE performed at Open Label (OL) End of Study/OL End of Dosing (EOS) visits. 


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b. Symptom-directed physical examination. 
c. Temperature, pulse, respiration, blood pressure performed at the following times: pre-dose at all visits; at 1, 2, 3, 4h (± 5 min), 6h 
and 8h (± 10 min) post-dose on OL Cycle 1 Day 1 and at OL Follow-up. 
d. See list of parameters in Appendix C. 
e. ECG at pre-dose at all visits; and at 2, 4, and 6h (± 10 min) post-dose on OL Cycle 1 Days 1 and 8; and at OL Follow-up. 
f. 
Performed pre-dose on Day 1 of each OL cycle, and at OL Follow-up. 
g. Day 1 of odd-numbered cycles, unless waived by the Sponsor (selected sites only). 
h. For subjects with measurable viral load at the Baseline Visit; on Day 1 of OL odd-numbered cycles only and at OL EOS. 
i. 
CT scan or MRI at the end of OL even-numbered cycles. If performed at +1 day after day 28, CT/MRI scan must be performed 
before administration of the morning dose of that day). 
j. 
End of Study OL visit timeframe is of 2 days since the last administered dose of IMP. 
 
 


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6. STUDY ENDPOINTS 
Baseline typically refers to Day 1 of Cycle 1 and Screening refers to the Pre-Study Visit. 
For some variables, Baseline is Cycle 1 Day 1 unless the assessment was performed at 
Screening which was ≤ 3 days prior to Cycle 1 Day 1, in which case the assessment was 
not to be repeated (footnotes ‘a’ and ‘c’ of Table 1-1). In the protocol and footnotes 
above, some assessments are given as performed at Day 28 or 29 of a cycle; consistent 
with the table above and the CRFs, these assessments are described below as being 
performed at Day 1 of the following cycle.  
 
Tumor assessments performed at the End of Study/ End of Dosing (EOS) Visit, the 
Follow-up Visit, and Unscheduled Visits will be assigned to the next cycle for calculation 
of summary statistics. 
 
The subjects who are still on blinded treatment when Amendment 5 is approved will be 
switched to open-label treatment at their next scheduled visit. The first day of open-label 
study drug dosing will be considered Day 1 (OL) of the trial. During this visit, the OL 
Cycle 1 Day 1 for OL procedures will be performed (Table 1-2). During the OL period, 
clinic visits will take place within ± 2 working days of the scheduled day; during these 
visits, assessments will be performed prior to administration of the study drug dose for 
that day. 
6.1 EFFICACY ASSESSMENTS 
Tumor response will be assessed at the Pre-Study Visit, Day 1 of odd-numbered cycles, 
and at the follow-up visit using Response Evaluation Criteria In Solid Tumors (RECIST 
v1.1) from Eisenhauer et al. (2009), presented in Appendix A of the protocol, and further 
described below in Appendix B. In general, target lesions will be assessed as Complete 
Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) 
and non-target lesions will be assessed as Complete Response (CR), Incomplete 
Response/Stable Disease (SD), or Progressive Disease (PD). Tumor responses from 
target lesions and from non-target lesions will be used to determine Overall Response as 
described in Appendix B. If the Overall Response is CR or PR, tumor assessments are to 
be repeated within 4 weeks.  Overall Response will be tabulated by cycle and treatment; 
the responses for target lesions and non-target lesions will be included in listings, but will 
not be tabulated. If Overall Response of PD is observed at any time, the patient will not 
automatically be discontinued. Further imaging or target lesion measurements will not be 
required and all other trial visits and procedures will continue.  
 
If assessments are made after the Overall Response of PD is recorded, then the Overall 
Response at all subsequent cycles will be PD and will be included at every cycle for 
which the Overall Response is recorded through Cycle 11 (see Section 7.2).  
6.1.1 TIME TO EVENT ENDPOINTS 
The primary efficacy endpoint is Overall Survival (OS), the time from Baseline to death 
due to any cause, calculated as date of death- date of Cycle 1 Day 1+1. Secondary time-
to-event endpoints are: 


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 TTP: the time from Baseline to the first Overall Response of PD, calculated as 
date of first PD - date of Cycle 1 Day 1+1, and  
 PFS: the time from Baseline to the first Overall Response of PD or death due to 
any cause if the subject dies without experiencing PD, calculated as date of first 
PD or death - date of Cycle 1 Day 1+1.  
6.1.2 TUMOR RESPONSE 
The secondary endpoints which are based directly on tumor response are: 
 ORR (OR Rate): proportion of subjects who have CR or PR,  
 DCR (DC Rate): proportion of subjects who have CR, PR, or SD, and 
 Best Overall Response during the duration of the study. 
(The best overall response for each subject is the best response recorded from the 
start of the study treatment until the end of study, in the order of CR, PR, SD, or 
PD from best to worst.) 
6.1.3 EXPLORATORY EFFICACY 
Laboratory parameters associated with hepatic dysfunction and cirrhosis (ALT, AST, 
bilirubin, and albumin levels, prothrombin time (PT), and International Normalized Ratio 
(INR)) will be assessed every cycle and will be considered exploratory efficacy variables. 
 
The effect of CF102 on α-fetoprotein (alpha-fetoprotein; AFP) will be assessed. AFP 
levels will be assessed at Baseline and on Day 1 of each subsequent cycle.  
 
Liver chemistry tests and viral load will be presented as exploratory efficacy variables, as 
will WBC A3AR expression. Viral load for Hepatitis B Virus (HBV) and Hepatitis C 
Virus (HCV) will be assessed at Baseline, at Day 1 of each subsequent odd cycle, at the 
end of dosing, and at the Follow-up visit for subjects with positive serology at Screening. 
 
6.2 SAFETY EVALUATIONS 
Safety parameters assessed throughout the trial include adverse events, ECOG 
performance status, vital signs, weight, physical examinations, laboratory parameters 
including thyroid functions, ECG, and concomitant medications. Any clinically 
significant change from baseline in a laboratory parameter will be reported as an AE. 
Liver chemistry tests and viral load will be presented as exploratory efficacy variables.  
 
At each visit, all AEs will be recorded in the appropriate section of the CRF and will be 
evaluated by the Investigator. The minimum information required for each AE includes 
the following:  


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 Type of event 
 Duration (start and end dates) 
 Severity  
 Seriousness 
 Relationship to study drug (Unrelated, Possibly Related, Probably Related, or 
Related) 
 Action taken 
 Outcome. 
 
In most cases, the CTCAE v4.0 criteria will preferably be used to grade severity; 
however, if an AE is not listed in the CTCAE, the following grading scale may be used: 
Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), Life-Threatening (Grade 4), or 
Fatal (Grade 5). 
 
7. STATISTICAL CONSIDERATIONS AND DATA ANALYSIS 
Tables and data listings will be prepared using SAS Version 9.0 or higher. A subject’s 
Baseline value for a specified variable will be the measurement for that variable taken on 
Day 1 of Cycle 1, unless the pre-study assessment was performed within 3 days prior to 
baseline. In the latter case, assessments do not need to be repeated prior to initiation of 
dosing for Physical Examination, Body Weight, Clinical Laboratory testing, Pregnancy 
Test, and ECOG PS, as noted in the Schedule of Procedures in Section 5 and the Baseline 
value will be the value at Screening.  
 
For any variable with Change From Baseline (CFB) calculated, CFB will be calculated as 
CFB = Value at Post-Baseline visit – Value at Baseline. 
If the final pre-treatment assessment was performed at Screening, prior to Baseline, then 
CFB is defined as the difference between the value at the post-Baseline visit and the 
value at Screening. 
 
Simple descriptive statistics for continuous data are: n (number of non-missing 
observations), mean, standard deviation, maximum, median, and minimum. Categorical 
data will be summarized by the number and percentage of subjects in each category. The 
data will be summarized upon completion of the final subject. All data collected for the 
OL period will be listed and select variables will be summarized. Listings and summaries 
for the OL period will be presented separately and a separate SAP will be prepared. The 
following pertains to the analyses and summaries for the DB period. 
 
 


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7.1 ANALYSIS POPULATIONS 
Analyses will be conducted using the populations described below. 
 
The Safety Population consists of all subjects who received at least one dose of study 
medication. Analyses of safety assessments will be performed using the Safety 
Population.  
 
The Intent-To-Treat (ITT) Population is defined as all subjects in the Safety 
Population with any post-Baseline assessment recorded. Exclusion of subjects from the 
ITT Population will be determined prior to unblinding. All efficacy analyses will be 
performed using the ITT Population.  
 
The Per Protocol (PP) Population is defined as all subjects in the ITT Population with 
no major protocol deviations, including major violations of inclusion and exclusion 
criteria and violation of RECIST requirements regarding the number of target lesions at 
Screening (Appendix B). Exclusion of subjects from the PP Population will be 
determined prior to unblinding. Tumor response (Sections 6.1.2 and 7.6.4) will be 
analyzed for the PP Population. 
 
7.2 GENERAL ANALYSIS 
The following standards will be applied for analyses unless otherwise specified. Simple 
descriptive statistics for continuous data are: n (number of non-missing observations), 
mean, standard deviation, maximum, median, and minimum. Categorical data will be 
summarized by the number and percentage of subjects in each category. Summaries of 
efficacy variables will be presented by visit through end of Cycle 11. Best Overall 
Response will be summarized once for the entire study. All data will be listed for the 
Safety Population, sorted by investigator number, subject number and, where appropriate, 
by visit, including data from visits after Cycle 11. The choice of Cycle 11 as the final 
time for tabulation will be finalized prior to unblinding. Tumor assessments performed at 
the EOS Visit, the Follow-up Visit, and Unscheduled Visits will be assigned to the next 
cycle and will be analyzed with that cycle. Tumor responses recorded on the CRF will be 
listed. Other data from Unscheduled Visits will not be summarized, except for AEs. 
 
7.3 SUBJECT DISPOSITION 
The total number of subjects will be presented with the number and percentage of 
subjects in each analysis population by treatment and overall. The number and percentage 
of subjects who completed the study, who discontinued, and primary reason for 
discontinuation will be summarized by treatment for the Safety Population. 
 


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7.4 DEMOGRAPHICS AND MEDICAL HISTORY 
7.4.1 DEMOGRAPHICS 
Demographic parameters, including age, sex, and origin, will be summarized for the 
Safety Population by treatment and overall. Age will be computed as (the number of days 
from Date of Birth to Date of Screening Visit)/365.25. After unblinding, it was decided to 
include the frequency distribution of Child-Pugh (CP) Score at Screening (7, 8, or 9) in 
the table of demographics and baseline characteristics. The CP Score for Subject 311-003 
was recorded as 6, but this was corrected to 7 after unblinding. 
7.4.2 HCC DISEASE HISTORY AND PRIOR THERAPIES 
HCC disease history includes  
 date of initial HCC diagnosis and staging,  
 date of most recent relapse and/or re-staging,  
 method used for diagnosis (histology / cytology or American Association 
for the Study of Liver Diseases (AASLD) Practice Guideline algorithm),  
 history of viral hepatitis, including date of diagnosis,  
 hepatitis B and hepatitis C virus serology (positive or negative), with the last date 
of testing, and  
 known complication(s) of cirrhosis and/or portal hypertension. 
 
History of viral hepatitis is recorded as “Yes, Hepatitis B”; “Yes, Hepatitis C”; “No”; or 
“Not known”, with the date of diagnosis recorded for the first two responses, both of 
which are possible. The summary statistics will include the counts and percentages for 
each of the four possible responses by treatment for the Safety Population.  
 
Known complication(s) of cirrhosis and/or portal hypertension are reported on the CRF 
as “Ascites”, “Esophageal varices with bleeding”, or “Other (specify)”. If none of these 
responses are selected, then the response should be reported as “None”. 
 
Prior therapies include  
 modality, 
 start and stop dates of treatments, 
 numbers of cycles, and  
 best response to each treatment. 
The number of subjects reporting the use of a modality at least once will be summarized 
by treatment for the Safety Population. Other variables pertaining to HCC disease history 
and prior therapies will be listed for the Safety Population. 
 
A table of the number of target hepatic lesions and the number of target non-hepatic 
lesions (Appendix B) at Screening for the Safety Population will be presented. 
 
A table of the incidence of Extrahepatic Spread (EHS), Portal Vein Thrombosis (PVT) at 
Baseline, including either EHS or PVT (“Yes” or “No”), will be provided. 
 


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7.4.3 MEDICAL HISTORY  
Medical history, excluding past HCC, cirrhosis, and viral hepatitis-related history, will be 
summarized using frequencies and percentages of subjects with a finding or procedure for 
each body system (or “None”) by treatment for the Safety Population by treatment and 
overall. “Other” will be listed but will not be included in the summaries. 
 
7.5 MEDICATION AND TREATMENT ANALYSIS 
7.5.1 COMPLIANCE AND EXPOSURE 
Compliance will be calculated as the number of total capsules dispensed (over the 
duration of the study) minus the total number of capsules returned, and then that quantity 
is divided by twice the duration of treatment in days. The duration of treatment is date of 
final dose minus date of Baseline + 1. If the date of final dose is missing or if the subject 
is still receiving treatment, the date of final dose will be imputed as described in 
Section 8. Descriptive statistics for compliance and the duration of treatment will be 
provided for the Safety Population by treatment. The summary statistics pooled across 
treatments will also be computed for duration of treatment, to be used in efficacy 
evaluations as described in Sections 7.6.1- 7.6.3. 
7.5.2 CONCOMITANT MEDICATIONS  
Concomitant and prior medications taken within 30 days prior to Screening Visit will be 
summarized by ATC Level 3. 
 
7.6 EFFICACY 
Efficacy will be assessed using the response based upon overall survival, time to 
progression, RECIST, and hepatitis viral load. Liver chemistry tests and viral load will be 
presented as exploratory efficacy variables, as will AFP and WBC A3AR expression. 
Summaries of efficacy variables by visit will be presented using visits through end of 
Cycle 11. Analyses of time to event (OS, TTP, and PFS) and Best Overall Response will 
not be restricted to visits through Cycle 11. All efficacy data will be listed. Binary 
response variables will not be analyzed using SAS PROC FREQ, which uses equal 
variances for the differences, as opposed to the unequal variances given below. 
 
 
 


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7.6.1 OVERALL SURVIVAL (OS) 
Overall survival (OS) is the time from Baseline to death due to any cause. OS will be 
summarized in months, which will be obtained by dividing OS in days by 30 days/month. 
Subjects who are alive at last contact will be considered censored at the date of last 
contact. Summary statistics (25th percentile, median, and 75th percentile) will be 
determined using the Kaplan-Meier (KM) estimate of the survival function. These 
summary statistics will be listed to one decimal place, rounded down such as the SAS 
FLOOR function. The KM curve for OS will be presented. The value of the KM curve 
for OS at the median duration of therapy (Section 7.5.1) will be presented. The between-
treatment comparison will be performed using the logrank test as the primary analysis. 
Between-treatment comparisons with respect to OS will be also performed using the 
proportional hazards model with AFP at Baseline and A3AR level at Baseline as 
covariates individually as secondary analyses, including the hazard ratio and the 95% 
confidence interval for the hazard ratios for both treatment and the covariate. Additional 
details are given in Section 9. 
7.6.2 TIME TO PROGRESSION (TTP) 
Time to Progression (TTP) is the time from Baseline to the first Overall Response of 
Progressive Disease (PD), computed as in Section 6.1.1. TTP will be summarized in 
months, which will be obtained by dividing TTP in days by 30 days/month. Subjects who 
do not have an Overall Response of PD by the time of last contact will be considered 
censored at the date of last contact; subjects who died without experiencing PD will be 
censored at the day of death. Summary statistics (25th percentile, median, and 75th 
percentile) will be determined using the KM estimate of the survival function for TTP. 
These summary statistics will be listed to one decimal place, rounded down such as the 
SAS FLOOR function. The KM curve for TTP will be presented. The value of the KM 
curve for TTP at the median duration of therapy (Section 7.5.1) will be presented. The 
between-treatment comparison will be performed using the logrank test. Additional 
details are given in Section 9. 
7.6.3 PROGRESSION-FREE SURVIVAL (PFS) 
Progression-free Survival (PFS) is the time from Baseline to the first Overall Response of 
Progressive Disease (PD) or death due to any cause if the subject dies without 
experiencing PD, computed as in Section 6.1.1. PFS will be summarized in months, 
which will be obtained by dividing PFS in days by 30 days/month. Subjects who are alive 
without experiencing an Overall Response of PD at the time of last contact will be 
considered censored at the date of last contact. Summary statistics (25th percentile, 
median, and 75th percentile) will be determined using the KM estimate of the survival 
function for PFS. These summary statistics will be listed to one decimal place, rounded 
down such as the SAS FLOOR function. The KM curve for PFS will be presented. The 
value of the KM curve for PFS at the median duration of therapy (Section 7.5.1) will be 
presented. The between-treatment comparison will be performed using the logrank test. 
Additional details are given in Section 9. 


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7.6.4 TUMOR RESPONSE 
The Objective Response Rate (ORR) is the percentage of subjects who achieved either 
CR or PR. ORR will be summarized using counts and percentages for the ITT Population 
by treatment and cycle. The between-treatment comparison will be performed using the 
normal approximation to the binomial distribution (NAB) with unequal variances, as 
follows. 
 
For each cycle, let pCF and p0 denote the proportions of subjects who experienced CR or 
PR based on nCF and n0 subjects for CF102 and Placebo, respectively, and let  
Z=(pCF-p0)/(pCF(1-pCF)/nCF + p0(1-p0)/n0)1/2. 
Then the corresponding p-value is p=2*(1-PROBNORM(ABS(Z))). 
 
The Disease Control Rate (DCR) is the percentage of subjects who achieved either CR, 
PR, or SD. DCR will be summarized using counts and percentages for the ITT Population 
by treatment and cycle. The between-treatment comparison will be performed using the 
(NAB), similar to that for ORR.  
 
For each subject, the Best Overall Response during the duration of the study will be 
determined and will be summarized using counts and percentages for the ITT Population 
by treatment. The between-treatment comparison will be performed using the NAB, for 
both the percentage of subjects who achieved either CR or PR (similar to ORR) and the 
percentage of subjects who achieved either CR, PR, or SD (similar to DCR). 
7.6.5 BIOMARKERS 
The biomarker α-fetoprotein (AFP) will be assessed at Baseline, at Day 1 of each cycle, 
and at the follow-up visit. Summary statistics for AFP levels and CFB in AFP levels will 
be provided for the ITT Population by treatment and visit. Between-treatment 
comparisons will be performed by visit using Analysis of Covariance (ANCOVA) with 
CFB as the dependent variable and Baseline as the covariate. Summary statistics for AFP 
and CFB in AFP will be provided for each level of Overall Response for the ITT 
Population by treatment. Distribution of Overall Response will be presented for subjects 
with AFP levels <20, 20-200, or >200 ng/mL and for subjects with AFP levels above or 
at most the pooled median by treatment and cycle; the percentages will be calculated 
using number of subjects within each category defined by AFP levels as the denominator 
for each treatment. 
 
WBC A3AR expression will be assessed at Baseline and at Day 1 of each odd-numbered 
cycle. Summary statistics for WBC A3AR expression and CFB in WBC A3AR expression 
will be provided for the ITT Population by treatment and visit. Summary statistics for 
CFB in WBC A3AR expression will be provided for each level of Overall Response for 
the ITT Population by treatment. To assess the relationship between Overall Response 
and changes in WBC A3AR at each visit, the distribution of Overall Response will be 
presented for subjects with WBC A3AR less than the pooled median and for subjects with 
WBC A3AR at least the pooled median at each post-baseline visit. 


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7.6.6 CHEMISTRY AND COAGULATION PARAMETERS 
The following laboratory parameters will be examined as exploratory efficacy variables: 
• alanine aminotransferase (ALT) 
• albumin 
• aspartate aminotransferase (AST) 
• bilirubin (direct and total) 
• International Normalized Ratio (INR) 
• prothrombin time (PT). 
 
The above variables and CFB for each variable will be summarized by treatment and visit 
for the ITT Population. Between-treatment comparisons will be performed by visit using 
ANCOVA with CFB as the dependent variable and the Baseline value of the variable as 
the covariate. These variables will be listed for the Safety Population with the other 
laboratory parameters. 
 
7.6.7 HEPATITIS VIRAL LOAD 
Viral load for Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) for subjects with 
positive serology at Screening will be summarized using summary statistics for log-
transformed values using the base 10 logarithm, which will be presented by treatment and 
visit for the ITT Population. Between-treatment comparisons will be performed by visit 
using ANCOVA with CFB for log-transformed values as the dependent variable and 
Baseline as the covariate. These variables (viral load (IU/mL) and log-transformed viral 
load) will be listed for the Safety Population. Any viral load recorded for subjects who do 
not have positive serology at Screening will not be included in tables but will be included 
in listings only. 
 
 
 


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Protocol CF102-201HCC  
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7.6.8 SUBGROUP ANALYSES  
After unblinding, it was decided to perform various subgroup analyses of OS. The 
subgroup analyses will be performed by the following assessments at Screening or 
Baseline:  
CP Score at Screening (7, 8, 7+8, or 9),  
Sex,  
ECOG PS at Screening (0 or 1+2),  
AFP (≤400 ng/mL or >400 ng/mL) at Baseline,  
Prior Locoregional therapy (HCC Prior Therapies of Radiation or 
Chemoembolization =Yes, Otherwise =No),  
EHS (Yes or No), PVT (Yes or No), and Either EHS or PVT (Yes or No), 
History of HBV (Known history of HBV=Yes or No),  
History of HCV (Known history of HCV=Yes or No),  
Diagnostic Procedure (Cytology/histology or AASLD), and  
Country (based on the first digit of the site number, given as Bulgaria=1, Serbia=2, 
Israel=3, Romania=5, or United States=7).  
 
The subgroup analyses will be performed as univariate analyses within each level of the 
corresponding subgrouping variable. For each subgrouping variable, the between-
treatment comparisons will be performed using the logrank test (Section 7.6.1). Each 
analysis will include the hazard ratio with the corresponding 95% confidence interval 
from proportional hazards model with no additional covariates and the p-value (Chi-
Square), as described in Section 9. The subgroup analyses do not include a plot of each 
KM curve, except for the analyses by CP Score at Screening (CP=7, CP=8, or CP=7 
or 8), and do not include the value of the KM curve at the median duration of therapy, 
provided in the analyses for the ITT Population.  
 
History of viral hepatitis is recorded as “Yes, Hepatitis B”; “Yes, Hepatitis C”; “No”; or 
“Not known”, with the date of diagnosis recorded for the first two responses, both of 
which are possible. If both of these responses are recorded, then the response for both 
History of HBV and History of HCV will be considered “Yes”. Subjects with responses 
of “Not known” will be excluded from the subgroup analyses using history of viral 
hepatitis. 
 
Subgroup analyses for other time-to-event variables or tumor response variables may be 
presented as further exploratory analyses after review. 
 
 


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Protocol CF102-201HCC  
Statistical Analysis Plan 
 
 
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7.7 SAFETY ANALYSES 
Safety data consist of adverse events (AEs), laboratory tests including thyroid functions, 
vital signs and weight, and physical examinations. Summaries of safety data will be 
conducted on all subjects in the Safety Population. Missing safety data will not be 
imputed. Summaries of all safety variables by visit will be presented for visits at which 
there are at least 4 subjects in either treatment group. Summaries of AEs, deaths, SAEs, 
and Discontinuation due to AE will not be restricted to visits with at least 4 subjects in 
either treatment group. All safety data will be listed. 
7.7.1 ADVERSE EVENTS 
The original reported (verbatim) terms used by the Investigator to identify adverse events 
in the CRFs will be entered into the database and coded by Preferred Term using the 
Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary (MedDRA 
MSSO, Reston, Virginia USA). Adverse events will then be grouped by MedDRA 
Preferred Term (PT) into frequency tables according to System Organ Classification 
(SOC).  
  
An adverse event that started during the treatment period (on or after the day of the 
baseline visit) or that was present at Baseline and increased in severity during the 
treatment period will be considered a treatment-emergent adverse event (TEAE). Events 
ending prior to the day of the baseline visit and events present at Baseline that do not 
increase in severity during treatment will be considered as Baseline adverse events and 
will not be included in the presentation of TEAEs. If the date of a new AE does not allow 
for determination of whether the AE is treatment emergent, it will be assumed to be a 
TEAE. 
 
The number and percentage of subjects experiencing TEAEs will be presented for the 
Safety Population for each body system and preferred term by treatment, and for each 
severity and relationship to study medication. When an adverse event occurs more than 
once, the maximum severity grade and relationship will be counted. For severity, only 
“Mild” and “Moderate” will be included for all SOCs and PTs; “Severe”, “Life-
Threatening”, or “Fatal” will be included for SOCs and PTs only when such are recorded 
for severity. Similarly, only “Possibly Related” and “Not Related” will be included for all 
SOCs and PTs; “Definitely Related” and “Probably Related” will be included for SOCs 
and PTs when such are recorded for relationship. 
 
Serious adverse events and discontinuations due to an adverse event will be provided in 
separate listings for the Safety Population. Each serious adverse event (SAE) will be 
listed for subjects in the Safety Population.  


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7.7.2 LABORATORY TESTS 
Laboratory tests (hematology, clinical chemistry, coagulation, urinalysis, and thyroid 
functions) will be performed at the timepoints specified in Appendix C, which also 
contains a complete list of all clinical laboratory tests. Clinical laboratory evaluations and 
CFB for each laboratory value will be listed and summarized using descriptive statistics 
by treatment and visit for visits with at least 4 subjects in either treatment group for the 
Safety Population. If a laboratory test is repeated during a visit, only the first values will 
be included in the summary; all values will be included in the listings. Clinically 
significant (CS) out-of-range laboratory values should be recorded as AEs. ALT (Alanine 
Aminotransferase; SGPT) and AST (Aspartate Aminotransferase; SGOT) are referred to 
as ALAT (SGPT) and ASAT (SGOT), respectively, in the listing of Blood Chemistry 
parameters. Urinalysis laboratory values will be listed only and CFB will not be 
computed. Laboratory assessments that are considered exploratory efficacy variables 
(Section 7.6.7) will be presented both as efficacy variables and laboratory variables, 
through Cycle 11 when considered exploratory efficacy variables and for all visits when 
considered safety variables. 
7.7.3 ECOG PERFORMANCE STATUS 
ECOG Performance Status (PS) is an assessment using a five-point scale, with 
0= Normal activity,…, 5=100 % bedridden; details are given in Appendix D. ECOG PS 
will be recorded at Pre-study visit, Day 1 of Cycle 1 (Baseline), Day 1 of each subsequent 
cycle, and at Follow-up. ECOG PS and categories of CFB in ECOG PS (decreased, no 
change, increased) will be presented for the Safety Population by treatment and cycle for 
cycles with at least 4 subjects in either treatment group.  
7.7.4 VITAL SIGNS AND WEIGHT 
Vital signs will be recorded at Days 1 and 15 of each cycle, Day 8 of Cycle 1, Hours 1, 2, 
3, 4, 6 and 8 on Cycle 1 Day 1, and at Follow-up. Systolic blood pressure (mmHg), 
diastolic blood pressure (mmHg), respiratory rate (breaths/min), pulse (beats/min), oral 
temperature (degrees C), and CFB for each of these vital signs will be listed and 
summarized using descriptive statistics for the Safety Population by treatment and visit 
for visits with at least 4 subjects in either treatment group. Height (cm) will be recorded 
at the Pre-Study Visit only and will be included in listings only. Body weight (kg) will be 
recorded at Days 1 and 15 of each cycle, Day 8 of Cycle 1, and at Follow-up; BMI 
(kg/m2) will be computed for each of these visits using the height recorded at the Pre-
Study Visit. 
 
 
 


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7.7.5 ECG PARAMETERS 
A resting 12-lead electrocardiogram (ECG) will be performed at the Pre-Study visit, 
Days 1 and 15 of all cycles, Day 8 of Cycle 1, and at 2, 4, and 6 hours post-dose on Day 1 
of Cycle 1, and at Follow-up. ECG interval data (Heart Rate [HR], PR, QRS, QT) and the 
corresponding CFBs will be listed and summarized using descriptive statistics for the 
Safety Population by treatment and visit for visits with at least 4 subjects in either 
treatment 
group. 
QTc 
will 
be 
computed 
using 
Fridericia’s 
correction, 
QTcF=QT*(HR/60)1/3. QT will not be summarized and will be included in the listing 
only. ST Segment (normal or abnormal), Cardiac Rhythm (normal or abnormal), and 
Overall Impression (normal, abnormal- NCS, or abnormal- CS) will be summarized using 
counts and percentages for the Safety Population by treatment and visit.  
7.7.6 PHYSICAL EXAMINATIONS 
A physical examination (PE) will be performed at every visit. A complete PE will be 
performed at the Pre-Study, Cycle 1 Day 1 (the Baseline Visit if the Pre-Study visit not 
performed within 3 days prior), and End of Study/End of Dosing (EOS) visits, including 
a thorough review of all body systems (general appearance, head/neck, ears/nose/throat, 
skin, chest/lungs, heart, abdomen, genitourinary, extremities, musculoskeletal, lymph 
nodes, neurological and other, specify) as well as measurement of weight (kg) and height 
(cm). At all other visits, a symptom-directed PE, including weight (kg), will be 
performed. If the Pre-Study visit is within 3 days of Cycle 1 Day 1, then no responses 
should be reported for Cycle 1 Day 1. 
 
At the Pre-Study visit, each body system, including “Other” (specify) if appropriate, will 
be assessed (Normal, Abnormal, or Not Done). At each visit after the Pre-Study visit, 
assessments will be recorded for any body systems with clinically significant (CS) 
changes from the PE conducted at the previous assessment (Normal, Abnormal, or Not 
Done), with details. The CRF indicates that these assessments should be recorded if the 
body system with a clinically significant change from the PE conducted at the previous 
assessment is “Abnormal”, with a description of the abnormality; these assessments 
should be recorded for any CS change from the previous PE, not just “Abnormal”, 
including a CS change from “Abnormal” to “Normal”. 
 
Assessments at the Pre-Study visit will be summarized by body system (Normal or 
Abnormal). Any subject with more than one assessment of “Other” will be counted once. 
Assessments recorded as “Not Done” will not be included in the table. Any description of 
an abnormality will be included in the corresponding listing. At each visit after the Pre-
Study visit, the number of subjects with at least one CS change from the PE conducted at 
the previous assessment will be summarized for the Safety Population by treatment and 
visit for visits with at least 4 subjects in either treatment group. Any body systems with a 
CS change from the PE conducted at the previous assessment will be included in the 
corresponding listing with the result and description. 
 


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30 
8. MISSING DATA 
Missing dates will be imputed only when the date is required to calculate the duration of 
an event for summary. As such, the only missing date that would need to be imputed is 
the date of final dose, required for calculation of duration of treatment. In such situations, 
the month and year would be recorded. For subjects who have completed dosing, the 
missing date of final dose will be imputed as the 15-th of the month; for subjects who are 
still receiving treatment, the missing date of final dose will be imputed as the date of the 
last completed visit. 
 
Missing data from intermediate visits for AFP, WBC A3AR, viral load, and laboratory 
assessments when considered exploratory efficacy variables will be imputed using Last 
Observation Carried Forward (LOCF). Missing data for the latter laboratory variables 
will not be imputed when examined with laboratory assessments as safety variables. Due 
to the nature of the study, there is no imputation due to discontinuation. 
 
The protocol specifies that certain assessments will not be repeated at Baseline (Cycle 1 
Day 1) if assessed at the Pre-Study visit <= 3 days prior to Cycle 1 Day 1, resulting in 
missing values for Baseline; in such cases, the missing value at Baseline will be imputed 
by the value from the Pre-Study visit.  
 
9. DIFFERENCES AND CHANGES FROM THE PROTOCOL 
The protocol states that disease history includes duration of prior sorafenib therapy, 
reason(s) for discontinuation of sorafenib, and if applicable, nature of intolerability to 
sorafenib. The duration is not directly collected, but can be computed from the start and 
stop dates, as provided for all prior HCC therapies. The reasons(s) for discontinuation, 
including nature of intolerability, were not collected for prior HCC therapies, including 
sorafenib. 
 
The protocol states that the listing of “dosing interruptions and dose reductions” will be 
provided. This listing is not provided, as these data were not specifically recorded, but are 
available as the “Action Taken” for AEs.  
 
In the protocol, ITT Population is defined as “all subjects in the Safety Population who 
have any post-Baseline efficacy data, including Liver Chemistry Tests and/or INR on 
Day 8 of Cycle 1, or death or discontinuation due to disease progression at any time.” 
According to SAP, ITT Population “is defined as all subjects in the Safety Population 
with any post-Baseline assessment recorded”. The difference has no impact, especially 
since no subjects were excluded from the ITT Population.  
 
Summaries of all safety variables by visit will be presented for visits at which there are at 
least 4 subjects in either treatment group. AEs, deaths, SAEs, and Discontinuation due to 
AE are not subject to this constraint. This restriction was not given in the protocol. 
 


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Summaries and analyses of efficacy variables by visit will be presented using visits 
through end of Cycle 11. Analyses of time to event (OS, TTP, and PFS) and Best Overall 
Response will not be restricted to visits through Cycle 11. This restriction was not given 
in the protocol. 
 
Analyses of time to event (OS, TTP, and PFS) originally included summary statistics 
(25th percentile, median, and 75th percentile) from the KM estimate of the survival 
function and the value of the KM curve at the median duration of therapy. The between-
treatment comparisons were performed using the logrank test. After unblinding, it was 
decided to include the hazard ratio with the corresponding 95% confidence interval from 
proportional hazards model with no additional covariates and the p-value (Chi-Square). 
The subgroup analyses of OS (Section 7.6.8) were not presented in the protocol. 
 
After unblinding, it was decided to present incidence of EHS and PVT at Baseline 
(Section 7.4.2), which are not given in the protocol. 
 
Any changes not presented in this or any subsequent version of the SAP will be described 
in the clinical study report. 
 
 


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10. APPENDICES 
10.1 APPENDIX A – CHILD-PUGH CLASSIFICATION OF 
SEVERITY OF LIVER DISEASE 
Child-Pugh classification of severity of liver disease is defined using the degree of 
ascites, plasma concentrations of bilirubin and albumin, prothrombin time, and the degree 
of encephalopathy.  
Class A (well-compensated disease): total score of 5-6. 
Class B (significant functional compromise): total score of 7-9. 
Class C (decompensated disease): total score of 10-15.  
 
Parameter 
Points Assigned 
1 
2 
3 
Ascites 
Absent 
Slight 
Moderate 
Bilirubin, mg/dL 
<2 
2-3 
>3 
Albumin, g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time 
* Seconds over control 
* INR 
 
1-3 
<1.7 
 
4-6 
1.7-2.3 
 
>6 
>2.3 
Encephalopathy 
None 
Grade 1-2 
Grade 3-4 
 
 
Parameter 
1 
2 
3 
Total bilirubin (μmol/L) 
<34 
34-50 
>50 
Albumin (g/L) 
>35 
28-35 
<28 
 
 
 


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10.2 APPENDIX B – DETERMINATION OF OVERALL 
RESPONSE 
Tumor status will be assessed at the Pre-Study Visit, Day 1 of odd-numbered cycles, and 
at the follow-up visit using Response Evaluation Criteria In Solid Tumors (RECIST), as 
presented in Appendix A of the protocol. The protocol states that tumor status will be 
assessed “at baseline and every 8 weeks thereafter (i.e., at the end of even-numbered 
cycles) by computed tomography (CT) scan or magnetic resonance imaging (MRI)”; 
however, the “baseline” assessment is performed at the Pre-Study Visit and the 
assessments of tumor status are recorded on CRF for Day 1 of odd-numbered cycles. 
 
Details regarding the calculation of Overall Response, and related variables, are 
presented here. The following details are from RECIST v1.1 (Eisenhauer et al. New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). 
European J Cancer. 45(2009): 228-247), the subsequent modification (Santoro et al. 
Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a 
randomized, placebo-controlled phase 2 study. Lancet Oncol. 2013; 14: 55-63), and the 
protocol. 
 
At Screening, target lesions are assessed: Up to 5 liver lesions and up to 2 lesions from 
other organs that can be accurately measured in at least one dimension with longest 
diameter ≥ 20 mm using conventional techniques (CT scan or MRI) or ≥ 10 mm with 
spiral CT scan. The LD for each target lesion should be compared to these minima, and 
any discrepancies noted for investigation and possible query. Lesions with LD less than 
these values and lesions from various sites which are “truly non-measurable” (Eisenhauer 
et al, 2009) are assessed as non-target lesions. 
 
Target Lesions 
The lesions identified at Screening as “Target Lesions” will be measured and the longest 
diameter (LD) of each target lesion is recorded, as well as the sum of the longest 
diameters. The sum of the longest diameters is recorded on CRF but should be re-
computed for accuracy; any discrepancy between this calculated value and the recorded 
sum will be noted for investigation and possible query, except in the case of minor round-
off discrepancies. In the latter case, the recorded value will be presented in the listings, 
but the calculated value will be used for all subsequent calculations. At each visit after 
Screening, the LDs for target lesions identified at Screening will be assessed; any new 
lesions will be recorded as such with “Non- Target Lesions” and discussed below.  
 
Listing 16.2.6.1.1 (Tumor Evaluations: Target Lesions) is the listing of assessment (LD) 
for each target lesion by subject and visit. Listing 16.2.6.1.2 (Summary of Target 
Lesions) is the listing of “Sum of Longest Diameters (mm), Smallest Sum On Study 
(mm), Percent Change from Smallest, Screening Sum on study, and Percent Change 
From Screening” by subject and visit for target lesions. These variables are recorded on 
CRF, but should be determined from the individual assessments reported in Listing 
16.2.6.1.1 as a check on accuracy. Inconsistencies, other than minor round-off, should be 
investigated. Percent Change from Smallest and Percent Change From Screening will be 
listed to one decimal place. 


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Based on results given in Listing 16.2.6.1.2, Response for Target Lesions can be 
determined as Complete Response (CR), Partial Response (PR), Stable Disease (SD), or 
Progressive Disease (PD) according to the following algorithm (from CRF). 
 
Pick the one response that applies from most recent assessment for Target Lesions:  
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. Note: the 
appearance of one or more new lesions is also considered 
progression. 
Stable Disease (SD) 
 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. 
Note that CR and PR are assessed relative to the baseline sum of diameters, whereas PD 
is assessed relative to the smallest sum of diameters. Note that “smallest sum on study” at 
any visit refers to sums prior to, and including, the visit of interest, including the baseline 
sum of diameters. 
 
Prior to unblinding, it was decided that subjects who can be assigned both PR and PD for 
target lesions at a cycle will be assigned PR. This will occur at a cycle whenever 
1.2*(Smallest Sum of LDs) ≤ Sum of LDs at Cycle ≤ 0.7* (Sum of LDs at Screening). 
For Subject 530-006 at Cycle 13, the Investigator recorded the response as PD and chose 
not to change the recorded response; both responses are provided in listings. 
 
Non-Target Lesions 
Listing 16.2.6.2 (Tumor Evaluations: Non-Target Lesions) is listing of status (Present, 
Absent, New, Progressive) for each non-target lesion by subject and visit. Based on 
results given in Listing 16.2.6.2, Response for Non-Target Lesions can be determined as 
Complete Response (CR), Non-CR/ Non-PD, or Progressive Disease (PD) according to 
the following algorithm (from CRF). The assessment also allows for “not evaluated”. 
 


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Protocol CF102-201HCC  
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Pick the one response that applies from most recent assessment for Non-Target Lesions:  
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis). Note: If tumor 
markers are initially above the upper normal limit, they 
must normalize for a patient to be considered in complete 
clinical response. 
Non-CR/ Non-PD:  
Persistence of one or more non-target lesions(s) or/and 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal 
progression should not normally trump target lesion status. 
It must be representative of overall disease status change, 
not a single lesion increase. 
 
Listing 16.2.6.3 (Tumor Response) includes Response for Target Lesions (based on 
results in Listing 16.2.6.1.2 and the above algorithm), Response for Non-Target Lesions 
(based on results in Listing 16.2.6.2 and the above algorithm), Overall Response, and 
Best Response. Overall Response is based on the Response for Target Lesions and the 
Response for Non-Target Lesions, according to the following algorithms, depending on 
whether subject has measurable disease or non-target lesions only. 
 
Overall Response - For Patients with Measurable Disease (i.e., Target Disease) 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD * 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression 
Note that this differs from the CRF; the corrections are given by the italicized entries. 
If Response for Non-Target Lesions=’CR’ or if there are no non-target lesions, then the 
Overall Response will be equal to the Response for Target Lesions.  
 


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Overall Response -For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesion 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD * 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised. 
 
Using the above tables, the overall response, given in Listing 16.2.6.3 is: 
Complete Response (CR), 
Partial Response (PR), 
Progressive Disease (PD), 
Stable Disease (SD), 
Non-CR/non-PD, or  
Unable to evaluate (NE) (with Comment). 
Analyses are based on these variables from Listing 16.2.6.3. Although these variables are 
recorded on the CRF, the algorithms should be programmed as a check on accuracy. 
Inconsistencies would be investigated.  
 
Other variables to be analyzed are 
ORR (OR Rate) = proportion of subjects who have CR or PR,  
DCR (DC Rate) = proportion of subjects who have CR, PR, or SD. 
Theses variables, ORR and DCR, are analyzed by visit and are also included in Listing 
16.2.6.3. 
 
 


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10.3 APPENDIX C – CLINICAL LABORATORY TESTS 
Except for the “OTHER” category, the following laboratory tests will be performed at 
Pre-Study Visit; Days 1 (i.e., the Baseline Visit if not performed ≤ 3 days prior), 8, and 
15 of Cycle 1; Days 1 and 15 of subsequent cycles; EOS; and Follow-Up. 
HEMATOLOGY TESTS 
 
CHEMISTRY TESTS 
 hematocrit 
 hemoglobin 
 platelet count 
 red blood cell count 
 white blood cell count and differential 
(absolute and percentage); neutrophils, 
lymphocytes, monocytes, eosinophils, 
basophils, and reticulocyte count 
 alanine aminotransferase (ALT)* 
 albumin* 
 alkaline phosphatase 
 aspartate aminotransferase (AST)* 
 bicarbonate 
 bilirubin (direct and total)* 
 blood urea nitrogen (BUN) 
 calcium 
 chloride 
 creatinine 
 glucose 
 lactate dehydrogenase (LDH) 
 phosphorus 
 potassium 
 sodium 
 total protein 
 uric acid 
 
URINALYSIS 
 
 glucose 
 ketones 
 occult blood 
 pH 
 protein 
 specific gravity 
 and, when indicated by dipstick 
abnormality, microscopic sediment 
evaluation 
 
COAGULATION PARAMETERS 
OTHER 
 International Normalized Ratio (INR)* 
 partial thromboplastin time (PTT) 
 prothrombin time (PT)* 
 
 alpha-fetoprotein (AFP): at baseline and 
Day 1 of each subsequent cycle*  
 thyroid functions (T3, T4, TSH) at Pre-
Study, Baseline, Day 1 of subsequent 
cycles, EOS, and Follow-up 
 serum pregnancy test: females of 
childbearing potential 
 hepatitis B and C viral load 
measurement every odd numbered cycle 
(where applicable)* 
*Exploratory efficacy variables 


Can-Fite BioPharma, Ltd. 
Protocol CF102-201HCC  
Statistical Analysis Plan 
 
 
38 
 
10.4 APPENDIX D – ECOG PERFORMANCE STATUS  
Level 
ECOG Performance Status 
0 
Normal activity 
1 
Symptoms but ambulatory 
2 
In bed < 50% of time 
3 
In bed > 50 % of time 
4 
100 % bedridden 
 
 
 


Can-Fite BioPharma, Ltd. 
Protocol CF102-201HCC  
Statistical Analysis Plan 
 
 
39 
10.5 APPENDIX E – CARDIAC FUNCTION 
CLASSIFICATION  
 
Cardiac Functional Classification 
NYHA 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical 
activity, e.g. shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g. walking short distances (20–100 m). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
 


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CF102-201HCC 
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A Phase 2, Randomized, Double-Blind, Placebo- Controlled Study of the 
Efficacy and Safety of CF102 in the Second-Line Treatment of Advanced 
Hepatocellular Carcinoma in Subjects with Child-Pugh Class B Cirrhosis 
 
 
 
Mock Tables and Listings 
Version 7.0 
 29 August 2019 
 
 
 
CONFIDENTIAL 
 
  
 


Can-Fite BioPharma, Ltd. 
 
 
CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 2 of  109 
 
Table of Contents 
1. 
INTRODUCTION ...................................................................................................... 5 
2. 
REPORTING CONVENTIONS................................................................................. 5 
3. 
OUTPUT TITLES ..................................................................................................... 6 
3.1. Table Titles......................................................................................................... 6 
3.2. Listing Titles ..................................................................................................... 10 
4. 
EXAMPLES ............................................................................................................ 12 
4.1. Table Examples ............................................................................................... 12 
Table 14.1.1 ........................................................................................................... 12 
Table 14.1.2 ........................................................................................................... 13 
Table 14.1.3 ........................................................................................................... 13 
Table 14.1.4.1 ........................................................................................................ 15 
Table 14.1.4.2 ........................................................................................................ 16 
Table 14.1.4.3 ........................................................................................................ 17 
Table 14.1.5 ........................................................................................................... 18 
Table 14.1.6 ........................................................................................................... 19 
Table 14.1.7 ........................................................................................................... 20 
Table 14.2.1 ........................................................................................................... 21 
Figure 14.2.1 .......................................................................................................... 22 
Figure 14.2.2 .......................................................................................................... 22 
Figure 14.2.3 .......................................................................................................... 24 
Table 14.2.2.1.1 ..................................................................................................... 25 
Table 14.2.2.2.1 ..................................................................................................... 26 
Table 14.2.3.1 ........................................................................................................ 27 
Table 14.2.3.2 ........................................................................................................ 28 
Table 14.2.3.3 ........................................................................................................ 29 
Table 14.2.4.1 ........................................................................................................ 30 
Table 14.2.4.2 ........................................................................................................ 31 
Table 14.2.4.3 ........................................................................................................ 32 
Table 14.2.4.4 ........................................................................................................ 33 
Table 14.2.5.1 ........................................................................................................ 34 
Table 14.2.6 ........................................................................................................... 35 
Table 14.2.7.1 ........................................................................................................ 36 
Figure 14.2.7.1 ....................................................................................................... 37 
Table 14.2.7.2 ........................................................................................................ 38 
Table 14.2.7.3 ........................................................................................................ 39 
Table 14.2.7.4 ........................................................................................................ 40 
Table 14.2.7.5 ........................................................................................................ 41 
Table 14.2.7.6 ........................................................................................................ 42 
Table 14.2.7.7 ........................................................................................................ 43 
Table 14.2.7.8 ........................................................................................................ 44 
Table 14.2.7.9 ........................................................................................................ 45 


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Table 14.2.7.10 ...................................................................................................... 46 
Table 14.3.1 ........................................................................................................... 47 
Table 14.3.2 ........................................................................................................... 48 
Table 14.3.3 ........................................................................................................... 49 
Table 14.3.4.1 ........................................................................................................ 50 
Table 14.3.4.2 ........................................................................................................ 51 
Table 14.3.5 ........................................................................................................... 52 
Table 14.3.6.1 ........................................................................................................ 53 
Table 14.3.6.4 ........................................................................................................ 54 
Table 14.3.7.1 ........................................................................................................ 55 
Table 14.3.7.2 ........................................................................................................ 56 
Table 14.3.8 ........................................................................................................... 57 
Table 14.3.9.1 ........................................................................................................ 58 
Table 14.3.9.2 ........................................................................................................ 59 
Table 14.3.10.1 ...................................................................................................... 60 
Table 14.3.10.2 ...................................................................................................... 61 
Table 14.3.11 ......................................................................................................... 62 
 
4.2. Listing Examples .............................................................................................. 63 
Listing 16.2.1.1 ....................................................................................................... 63 
Listing 16.2.1.2 ....................................................................................................... 64 
Listing 16.2.2.1 ....................................................................................................... 65 
Listing 16.2.2.2 ....................................................................................................... 67 
Listing 16.2.3.1 ....................................................................................................... 69 
Listing 16.2.3.2 ....................................................................................................... 70 
Listing 16.2.3.3.1 .................................................................................................... 71 
Listing 16.2.3.3.2 .................................................................................................... 72 
Listing 16.2.3.4 ....................................................................................................... 73 
Listing 16.2.3.5 ....................................................................................................... 74 
Listing 16.2.3.6 ....................................................................................................... 75 
Listing 16.2.4.1 ....................................................................................................... 76 
Listing 16.2.4.2 ....................................................................................................... 77 
Listing 16.2.5.1 ....................................................................................................... 78 
Listing 16.2.5.2 ....................................................................................................... 79 
Listing 16.2.6.1.1 .................................................................................................... 80 
Listing 16.2.6.1.2 .................................................................................................... 81 
Listing 16.2.6.2 ....................................................................................................... 82 
Listing 16.2.6.3.1 .................................................................................................... 83 
Listing 16.2.6.3.2 .................................................................................................... 84 
Listing 16.2.6.4 ....................................................................................................... 85 
Listing 16.2.6.5.1 .................................................................................................... 87 
Listing 16.2.6.5.2 .................................................................................................... 88 
Listing 16.2.7 .......................................................................................................... 89 
Listing 16.2.8.1 ....................................................................................................... 90 
Listing 16.2.8.2 ....................................................................................................... 92 
Listing 16.2.8.3 ....................................................................................................... 95 


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Statistical Analysis Plan Tables and Listings 
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Listing 16.2.8.4 ....................................................................................................... 97 
Listing 16.2.8.5 ....................................................................................................... 98 
Listing 16.2.8.6 ..................................................................................................... 100 
Listing 16.2.9.1 ..................................................................................................... 101 
Listing 16.2.9.2 ..................................................................................................... 102 
Listing 16.2.9.3 ..................................................................................................... 103 
Listing 16.2.10.1 ................................................................................................... 104 
Listing 16.2.10.2 ................................................................................................... 105 
Listing 16.2.11.1 ................................................................................................... 106 
Listing 16.2.11.2 ................................................................................................... 107 
Listing 16.2.12 ...................................................................................................... 108 
Listing 16.2.13 ...................................................................................................... 109 
 


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Statistical Analysis Plan Tables and Listings 
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1. INTRODUCTION 
This document is to be used in conjunction with the current Statistical Analysis Plan 
(SAP), protocol (Amendment 5, dated 6 November 2018), and corresponding CRFs.  
 
The following pertains to the double-blind period only. Shells for the open-label period 
will be presented with a separate SAP. 
 
Hyper-links are identified in this document as blue underlined text. 
2. REPORTING CONVENTIONS 
All output will be generated by SAS and exported into a Microsoft Word document in 
RTF format. All output will be in landscape orientation. Left and right margins will be 
1 inch from the side; the top and bottom margins will be 1.12 inches. Font size will be 
Arial 8 pt.   
 
The header containing the sponsor name (Can-Fite BioPharma, Ltd.) and protocol 
number (CF102-201HCC) will appear on the top left corner of each page of the output. 
The page number, in the format of “Page x of y”, will appear on the top right corner of 
the output, where y = last page of corresponding output. Horizontal lines will appear 
after the title, after the column headers and after the main body of the output.  
 
The header and the titles section will be separated by one line. After the header, there 
will be a blank line. The titles will be presented as:    
Line1:  
Table or Figure [number] 
Line2a: 
[title] 
Line2b: 
[subtitle, if applicable]  
Line3:  
[xxx] Population 
 
Footnotes will be placed after the main body of the table, under the horizontal line.  
Footnotes that need to reference a specific phrase will use a numeric convention 
(Example: 1, 2, 3). The last footnote will identify the listing or statistical appendix cross-
reference as follows: Source: Listing 16.2.x. The sources for each table are identified in 
Section 3.1, Table Titles. 
 
Table Format Specification 
Maximum and minimum values will be reported with the same number of decimal places 
as collected.  Means and medians will be reported to one additional decimal place. 
Standard deviations and standard errors will be reported to two decimal places more 
than the collected data. Percents will be reported with one decimal place. P-values will 
be rounded to three decimal places (e.g., “0.xxx”). If a p-value <0.001, then the p-value 
will be reported as “<0.001”. 
 
If the frequency is 0 or 1 for a category for calculation of a standard deviation or 
standard error, then enter ‘(NE)’ for calculation of the standard deviation or standard 
error and add a footnote (penultimate preceding Source) of ‘NE= Not Estimable’.  


Can-Fite BioPharma, Ltd. 
 
 
CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 6 of  109 
 
 
If the frequency for “Total” <2 for a categorical variable for either treatment group, or 
frequency is “Total” for any category, i.e. a percent of 100 for that category, for both 
treatment groups, then enter ‘NA’ for the p-value with a footnote (penultimate preceding 
“Source”) of ‘NA = Not Applicable’. 
 
Data in the tables are formatted as follows: 
 
 Text fields in the body of the tables and listings will be left-justified.  
 All numeric values between -1 and 1 are outputted with zero to the left of the 
decimal point (e.g. 0.12, 0.3). 
 Unless otherwise specified, percentage values are output with one digit to the 
right of the decimal point (e.g., 12.3, 4.5). Percentages that are > 0.0 and < 0.1 
(not 0.0) are reported as “< 0.1”. 
 When no data are available for a table, an empty page with the title will be 
produced with suitable text. Example:  THERE WERE NO SERIOUS ADVERSE 
EVENTS. 
 
For many variables assessed at Pre-Study Visit, Baseline=Cycle 1 Day 1 (or Pre-Study 
if <= 3 days prior to Cycle 1 Day 1) or if value at Cycle 1 Day 1 is missing. These are 
variables are identified with a footnote indicating this. 
 
Dates will be presented as recorded. All listings will include the Safety Population and 
will be sorted by site, subject, and cycle (if appropriate). Treatments are to be formatted 
as CF102 and Placebo in listings. 
 
3. OUTPUT TITLES 
3.1. 
Table Titles 
Table examples related to the following titles are located in the next section. Please 
footnote all information in the ‘Listing Source’ column for the corresponding table. 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 7 of 109   
 
 
 
 
 
 
 
 
Number 
 
Title of Table 
Analysis 
Population 
 
Listing Source 
 
DISPOSITION, DEMOGRAPHIC AND TREATMENT DATA 
 
 
14.1.1 
Analysis Populations 
Safety 
16.2.1.1, 16.2.1.2 
14.1.2 
Study Completion and Primary Reason for Withdrawal  
Safety 
16.2.1.1 
14.1.3 
Demographic and Baseline Characteristics 
Safety 
16.2.3.1 
14.1.4.1 
HCC History and Diagnosis 
Safety 
16.2.3.2, 16.2.3.3.1, 
16.2.3.5 
14.1.4.2 
Number of Target Lesions at Screening 
Safety 
16.2.6.1.1 
14.1.4.3 
Extrahepatic Spread (EHS) and Portal Vein Thrombosis (PVT) 
Safety 
16.2.3.3.2 
14.1.5 
Medical History (Excluding Past HCC, Cirrhosis, and Viral Hepatitis-Related 
History) 
Safety 
16.2.3.6 
14.1.6 
HCC Prior Therapies 
Safety 
16.2.3.4 
14.1.7 
Treatment Compliance and Duration of Treatment 
Safety 
16.2.4.1 
 
 
 
 
 
EFFICACY 
 
 
14.2.1 
Time to Event (months) 
ITT 
16.2.5.1 
 
Figure 14.2.1: Kaplan-Meier curve for OS 
ITT 
16.2.5.1 
 
Figure 14.2.2: Kaplan-Meier curve for TTP 
ITT 
16.2.5.1 
 
Figure 14.2.3: Kaplan-Meier curve for PFS 
ITT 
16.2.5.1 
14.2.2.1.1 
Overall Response Using RECIST Criteria 
ITT 
16.2.6.3.1 
14.2.2.1.2 
Overall Response Using RECIST Criteria 
PP 
16.2.6.3.1, 16.2.1.2 
14.2.2.2.1 
Best Overall Response 
ITT 
16.2.6.3.1 
14.2.2.2.2 
Best Overall Response 
PP 
16.2.6.3.1, 16.2.1.2 
 
 
 
 
14.2.3.1 
WBC A3AR expression 
ITT 
16.2.6.4 
14.2.3.2 
WBC A3AR expression by Overall Response 
ITT 
16.2.6.3.1, 16.2.6.4 
14.2.3.3 
Overall Response by CFB for WBC A3AR expression  
ITT 
16.2.6.3.1, 16.2.6.4 
14.2.4.1 
Alpha-fetoprotein (AFP)  
ITT 
16.2.6.4 
14.2.4.2 
Alpha-fetoprotein (AFP) by Overall Response 
ITT 
16.2.6.3.1, 16.2.6.4 
14.2.4.3 
Overall Response by Categorical Alpha-fetoproterin (AFP) 
ITT 
16.2.6.3.1, 16.2.6.4 
14.2.4.4 
Overall Response by CFB for Alpha-fetoproterin (AFP) 
ITT 
16.2.6.3.1, 16.2.6.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 8 of 109   
 
 
 
 
 
 
Number 
 
Title of Table 
Analysis 
Population 
 
Listing Source 
 
 
 
 
 
EXPLORATORY EFFICACY 
 
 
14.2.5.1 
Alanine aminotransferase (ALT)  
ITT 
16.2.8.2  
14.2.5.2 
Aspartate aminotransferase (AST) 
ITT 
16.2.8.2 
14.2.5.3 
Albumin 
ITT 
16.2.8.2 
14.2.5.4 
Bilirubin (direct) 
ITT 
16.2.8.2  
14.2.5.5 
Bilirubin (total) 
ITT 
16.2.8.2 
14.2.5.6 
International Normalized Ratio (INR) 
ITT 
16.2.8.3  
14.2.5.7 
Prothrombin time (PT) 
ITT 
16.2.8.3  
14.2.6 
Hepatitis Viral Load 
ITT 
16.2.3.3.1, 
16.2.6.5.1, 16.2.6.5.2 
 
 
 
 
 
SUBGOUP ANALYSES  - EFFICACY 
 
 
14.2.7.1 
 Overall Survival (OS; months) by Child-Pugh (CP) Score at Screening 
ITT 
16.2.3.1, 16.2.5.1 
 
Figure 14.2.7.1: Kaplan-Meier curve for OS, CP Score at Screening = 7 
ITT 
16.2.3.1, 16.2.5.1 
 
Figure 14.2.7.2: Kaplan-Meier curve for OS, CP Score at Screening = 8 
ITT 
16.2.3.1, 16.2.5.1 
 
Figure 14.2.7.3: Kaplan-Meier curve for OS, CP Score at Screening = 7 or 8 
ITT 
16.2.3.1, 16.2.5.1 
14.2.7.2 
Overall Survival (OS; months) by Sex  
ITT 
16.2.3.1, 16.2.5.1 
14.2.7.3 
Overall Survival (OS; months) by ECOG PS at Screening 
ITT 
16.2.9.3, 16.2.5.1 
14.2.7.4 
Overall Survival (OS; months) by Alpha-fetoprotein (AFP) at Baseline 
ITT 
16.2.6.4, 16.2.5.1 
14.2.7.5 
Overall Survival (OS; months) by Prior Locoregional Therapy 
ITT 
16.2.3.4, 16.2.5.1 
14.2.7.6 
Overall Survival (OS; months) by Either EHS or PVT 
ITT 
16.2.3.3.2, 16.2.5.1 
14.2.7.7 
Overall Survival (OS; months) by History of HBV 
ITT 
16.2.3.3.1, 16.2.5.1 
14.2.7.8 
Overall Survival (OS; months) by History of HCV 
ITT 
16.2.3.3.1, 16.2.5.1 
14.2.7.9 
Overall Survival (OS; months) by Diagnostic Procedure 
ITT 
16.2.3.2, 16.2.5.1 
14.2.7.10 
Overall Survival (OS; months) by Country  
ITT 
16.2.1.1, 16.2.5.1 
 
THE PREVIOUS SHOULD BE IN THE SAME ORDER AS IN TEXT 
 
 
 
 
 
 
 
SAFETY 
 
 
 
Adverse Events 
 
 
14.3.1 
Incidence of Treatment-Emergent Adverse Events  
Safety 
16.2.7 
14.3.2 
Incidence of Treatment-Emergent Adverse Events by Relationship  
Safety 
16.2.7 
14.3.3 
Incidence of Treatment-Emergent Adverse Events by Severity  
Safety 
16.2.7 
14.3.4.1  
Listing of Deaths  
Safety 
16.2.1.1, 16.2.5.1, 
16.2.7 
14.3.4.2 
Listing of Serious Adverse Events  
Safety 
16.2.7 
14.3.5 
Listing of Discontinuations due to Adverse Events 
Safety 
16.2.7 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 9 of 109   
 
 
 
 
 
 
Number 
 
Title of Table 
Analysis 
Population 
 
Listing Source 
 
 
 
 
 
Laboratory Values 
 
 
14.3.6.1 
Clinical Laboratory Evaluations: Hematology 
Safety 
16.2.8.1 
14.3.6.2 
Clinical Laboratory Evaluations: Blood Chemistry 
Safety 
16.2.8.2 
14.3.6.3 
Clinical Laboratory Evaluations: Coagulation 
Safety 
16.2.8.3 
14.3.6.4 
Clinical Laboratory Evaluations: Thyroid Function 
Safety 
16.2.8.5 
 
 
 
 
 
Other Safety 
 
 
14.3.7.1 
ECOG Performance Status (PS) 
Safety 
16.2.9.3 
14.3.7.2 
Change from Baseline in ECOG Performance Status 
Safety 
16.2.9.3 
14.3.8 
Vital Signs And Weight  
Safety 
16.2.9.1, 16.2.9.2 
14.3.9.1 
Electrocardiogram (ECG) Parameters  
Safety 
16.2.10.1 
14.3.9.2 
Categorical Electrocardiogram (ECG) Parameters 
Safety 
16.2.10.2 
14.3.10.1 
Physical Examination at Pre-Study Visit 
Safety 
16.2.11.1 
14.3.10.2 
Physical Examination 
Safety 
16.2.11.2 
14.3.11 
Prior and Concomitant Medications 
Safety 
16.2.12 
 
 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
Page 10 of 109   
 
 
 
 
 
 
3.2. 
Listing Titles 
 
 
Number 
Title of Listing 
16.2.1.1 
Completed and Discontinued Subjects with Primary Reason for Withdrawal 
16.2.1.2 
Subjects Excluded from Analysis Populations 
16.2.2.1 
Inclusion Criteria 
16.2.2.2 
Exclusion Criteria  
16.2.3.1 
Demographic and Baseline Characteristics 
16.2.3.2 
HCC Diagnosis 
16.2.3.3.1 
HCC History  
16.2.3.3.2 
Extrahepatic Spread (EHS) and Portal Vein Thrombosis (PVT) 
16.2.3.4 
HCC Prior Therapies 
16.2.3.5 
Cirrhosis / Virus Complications and Treatment 
16.2.3.6 
Medical History (Excluding Past HCC and Cirrhosis-Related History) 
16.2.4.1 
Study Drug Accountability and Treatment Compliance 
16.2.4.2 
Study Drug Accountability by Visit 
16.2.5.1 
Time to Event 
16.2.5.2 
Survival Follow-up Contact Dates 
16.2.6.1.1 
Tumor Evaluations: Target Lesions 
16.2.6.1.2 
Summary of Target Lesions 
16.2.6.2 
Tumor Evaluations: Non-Target Lesions 
16.2.6.3.1 
Tumor Response 
16.2.6.3.2 
Tumor Response (Investigator Assessments) 
16.2.6.4 
Biomarkers (AFP and WBC A3AR) 
16.2.6.5.1 
Hepatitis B Viral Load 
16.2.6.5.2 
Hepatitis C Viral Load 
 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
Page 11 of 109   
 
 
 
 
 
 
 
 
 
 
Number 
Title of Listing 
16.2.7 
Adverse Events 
16.2.8.1 
Clinical Laboratory Evaluations: Hematology 
16.2.8.2 
Clinical Laboratory Evaluations: Blood Chemistry 
16.2.8.3 
Clinical Laboratory Evaluations: Coagulation 
16.2.8.4 
Clinical Laboratory Evaluations: Urinalysis 
16.2.8.5 
Clinical Laboratory Evaluations: Thyroid Function 
16.2.8.6 
Pregnancy Test 
16.2.9.1 
Vital Signs 
16.2.9.2 
Weight, Height, and BMI 
16.2.9.3 
ECOG Performance Status 
16.2.10.1 
Electrocardiogram (ECG) – Continuous Variables 
16.2.10.2 
Electrocardiogram (ECG) – Categorical Variables 
16.2.11.1 
Physical Examination at Pre-Study Visit 
16.2.11.2 
Physical Examination 
16.2.12 
Prior and Concomitant Medications 
16.2.13  
Investigator Comments 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 12 of 109   
 
 
 
 
 
 
4. EXAMPLES 
4.1. 
Table Examples 
 
Table 14.1.1 
Analysis Populations 
 
 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Total 
(N=xx) 
Safety Population 
xx 
xx 
xx 
Bulgaria 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Serbia 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Israel 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Romania 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
United States 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Exclusions from ITT Population 
 
 
 
No Post-Baseline Tumor Assessment 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Reason 2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Total 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
ITT Population 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Bulgaria 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Serbia 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Israel 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Romania 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
United States 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Exclusions from PP Population 
 
 
 
Reason 1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Reason 2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Total 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PP Population 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Bulgaria 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Serbia 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Israel 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Romania 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
United States 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Percentages are calculated using the number of subjects in the Safety Population for each treatment (or Total) as the denominator. 
ITT= Intent-to-Treat 
PP=Per Protocol 
Country is based on the first digit of the site number (1=Bulgaria, 2=Serbia, 3=Israel, 5=Romania, or 7=United States). 
Source: Listings 16.2.1.1, 16.2.1.2   
Programming Notes: Any reasons for exclusion from ITT Population (other than “No Post-Baseline Tumor Assessment”) 
and reasons for exclusion from PP Population, and identification of subjects excluded, will be finalized prior to unblinding.  
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 13 of 109   
 
 
 
 
 
 
 
Table 14.1.2 
Study Completion and Primary Reason for Withdrawal  
Safety Population 
 
Status, n(%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Total 
(N=xx) 
 
 
 
 
Primary Reason for Withdrawal from Dosing 
 
 
 
Grade 3 toxicity considered by the Investigator to be at least “possibly” drug-related that does not resolve to 
Grade ≤ 1 within 7 days following interruption of treatment 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Grade 4 toxicity considered by the Investigator to be at least “possibly” drug-related 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Need for > 1 dose reduction 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Treatment interruption or delay for more than 14 days after the next scheduled dose due to an event unrelated 
to toxicity 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Subject withdrawal of consent for trial participation at any time, for any reason, and without prejudice 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Withdrawal of a subject by the Investigator, at his/her discretion, for any reason that the Investigator believes 
continuation of study drug therapy would not be in the subject’s best interest.   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
An intercurrent illness which, in the Investigator’s opinion, would prevent completion of trial-related evaluations 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Pregnancy 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Subject noncompliance with trial or follow-up procedures 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Termination of the trial by the Sponsor 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Total 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Primary Reason for Withdrawal from Trial 
 
 
 
Withdrawal of consent 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Termination of the trial by the Sponsor 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Death 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Total 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
Percentages are calculated using the number of subjects in the Safety Population for each treatment (or Total) as the denominator. 
Source: Listing 16.2.1.1 
 
 
Programming Note: Subjects should have response to either Primary Reason for Withdrawal from Dosing or Primary Reason for Withdrawal from 
Trial, but not BOTH. 
 
 
 
Table 14.1.3 
Demographic and Baseline Characteristics 
Safety Population 
 
Parameter (1) 
Statistic 
CF102  
Placebo 
Total 


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(N=xx) 
 (N=xx) 
(N=xx) 
Age (years) 
n 
xx 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
Sex, n (%) 
Male 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Female 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
xx 
 
 
 
 
 
Origin, n (%) 
White/Caucasian 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Black/African 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Oriental 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Child-Pugh Score, n (%) 
7 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
8 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
9 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
(1) Age is age at Screening. 
Percentages are calculated using the number of subjects in the Safety Population for each treatment (or Total) as the denominator. 
Source: Listing 16.2.3.1 
 
 
 
 


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Table 14.1.4.1 
HCC History and Diagnosis 
Safety Population 
 
Parameter 
 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Total 
(N=xx) 
History of Viral Hepatitis, n (%) (1) 
Yes – Hepatitis B 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Yes – Hepatitis C 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Not Known 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Hepatitis B Serology, n (%) 
Negative 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Positive 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
xx 
 
 
 
 
 
Hepatitis C Serology, n (%) 
Negative 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Positive 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
xx 
 
 
 
 
 
Complications, n (%) (1) 
None 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Ascites 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Esophageal varices with bleeding 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Diagnostic Procedure, n (%) (2) 
Cytology/histology 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
AASLD 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Percentages are calculated using the number of subjects in the Safety Population for each treatment (or Total) as the denominator. 
(1) Percentages may sum to more than 100% because more than one response is possible. 
(2) AASLD=American Association for the Study of Liver Diseases 
Source: Listings 16.2.3.2, 16.2.3.3.1, 16.2.3.5 
 
 
Programming Note:  Check that no subject has “None” for Complications with another response. 
 
 


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Table 14.1.4.2 
Number of Target Lesions at Screening  
Safety Population 
 
 
Non- Liver 
Number of 
Number of Liver Lesions 
 
Site Code (1) 
Non- Liver Lesions 
0 
1 
2 
3 
4 
5 
7 
Total 
CF102 (N=xx) 
None 
 
 
 
xx 
xx 
xx 
xx 
 
xx 
 
01 
1 
 
 
xx 
xx 
xx 
xx 
 
xx 
 
 
2 
xx 
xx 
xx 
xx 
 
xx 
 
xx 
 
02 
1 
 
xx 
xx 
xx 
 
xx 
 
xx 
 
 
2 
 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
10 
1 
 
 
xx 
xx 
xx 
xx 
 
xx 
 
99 
1 
 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
 
2 
xx 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
 
3 
 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
Total (2) 
 
xx 
xx 
xx 
xx 
xx 
xx 
 
xx 
Placebo (N=xx) 
None 
 
 
xx 
 
 
xx 
xx 
 
xx 
 
02 
0 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
1 
 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
04 
1 
 
xx 
 
 
xx 
xx 
 
xx 
 
 
2 
 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
99 
1 
 
xx 
xx 
 
 
xx 
 
xx 
 
 
2 
 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
 
3 
xx 
xx 
xx 
xx 
 
 
 
xx 
 
Total (2) 
 
xx 
xx 
xx 
xx 
xx 
xx 
 
xx 
Total (N=xx) 
None 
 
 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
01 
1 
 
 
xx 
xx 
xx 
xx 
 
xx 
 
 
2 
xx 
xx 
xx 
xx 
 
xx 
 
xx 
 
02 
0 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
1 
xx 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
 
2 
xx 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
04 
1 
 
xx 
 
 
xx 
xx 
 
xx 
 
 
2 
 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
10 
1 
 
 
xx 
xx 
xx 
xx 
 
xx 
 
99 
1 
 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
 
2 
xx 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
 
3 
xx 
xx 
xx 
xx 
xx 
xx 
 
xx 
 
Total (2) 
 
xx 
xx 
xx 
xx 
xx 
xx 
 
xx 
(1) Site Codes:  01 = Abdominal Wall, 02 = Adrenal, 03 = Bladder, 04 = Bone, 05 = Breast, 06 = CNS,  07 = Colon, 08 = Liver, 09 = Lung,  10 = Lymph Nodes, 
11 = Pancreas, 12 = Pelvis, 13 = Pleura, 14 = Rectum, 15 = Retroperitoneal Cavity, 16 = Retroperitoneum, 17 = Small Intestine, 18 = Uterus, 99 = Other 
(2) Number of non-liver lesions may not sum to Total due to subjects with more than one non-liver site. 
Source: Listing 16.2.6.1.1 
Programming Notes:  Do not skip numbers for liver lesions for 1 through 5. There should be no subjects with 0 liver lesions or more than 5 liver lesions; if these 
are observed, include them as above, but otherwise only 1 through 5. Include only non-zero counts. For non-liver lesions, exclude rows with no entries. If any 
subjects have only liver lesions, include “None” row as non-liver site code. The values will be the counts of lesions at “Screening” from Listing 16.2.6.1.1. 
 
 


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Table 14.1.4.3 
Extrahepatic Spread (EHS) and Portal Vein Thrombosis (PVT) 
Safety Population 
 
Parameter, n (%) 
 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Total 
(N=xx) 
Extrahepatic Spread (EHS) 
Yes  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
xx 
 
 
 
 
 
Portal Vein Thrombosis (PVT) 
Yes  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
xx 
 
 
 
 
 
Either EHS or PVT 
Yes  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
xx 
 
 
 
 
 
Both EHS and PVT 
Yes  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Percentages are calculated using the number of subjects for each treatment (or Total) as the denominator. 
 
Source: Listing 16.2.3.3.2 
 
 
Programming Note: “Either EHS or PVT”= “Yes” if EHS= “Yes” or PVT= “Yes” and otherwise “Either EHS or PVT”= “No”. 
“Both EHS and PVT”= “Yes” if EHS= “Yes” and PVT= “Yes” and otherwise “Both EHS and PVT”= “No”. 
 
 


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Table 14.1.5 
Medical History (Excluding Past HCC, Cirrhosis, and Viral Hepatitis-Related History) 
Safety Population 
 
Body System, n (%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Total 
(N=xx) 
None 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Allergy/Immunological 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Cardiovascular 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Dermatological 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
ENT 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Gastrointestinal/ Hepatobiliary 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Hematological/ Lymphatic 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Metabolic/Endocrine 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Musculoskeletal 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Neoplastic 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Neurological/ Psychiatric 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Pulmonary 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Renal/Urological 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Reproductive 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
Counts represent the number of subjects with a finding or procedure recorded for each body system or None. 
Percentages are calculated using the number of subjects in the Safety Population for each treatment (or Total) as the denominator. 
Source: Listing 16.2.3.6 
 
Programming Notes: Present body systems alphabetically after “None”.  
Check that no subject has “None” for Body System with another response. 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.1.6 
HCC Prior Therapies 
Safety Population 
 
Prior Therapy, n (%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Total 
(N=xx) 
01 = Surgery 
 
 
 
Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Total 
xx 
xx 
xx 
 
 
 
 
02 = Radiation 
 
 
 
Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Total 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The entries are the number (and percentage) of subjects reporting the use of a modality at least once. 
Percentages are calculated using the number of subjects in the Safety Population for each treatment (or Total) 
as the denominator. 
Source: Listing 16.2.3.4 
 
 
Programming Note: Continue for Modality Codes:  03 = Chemotherapy, 04 = Immunotherapy, 
05 = Hormonal therapy, 06 = Targeted Therapy (sorafenib), 07 = Chemoembolization, 
08 = Anti-viral therapy, 09 = Other. 
 
 
 
 


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Table 14.1.7 
Treatment Compliance and Duration of Treatment 
Safety Population 
 
 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Total 
(N=xx) 
Compliance Rate, % (1)  
 
 
 
n 
xx 
xx 
xx 
Mean (SD) 
xx.xx (xx.xxx) 
xx.xx (xx.xxx) 
xx.xx (xx.xxx) 
Median 
xx.xx 
xx.xx 
xx.xx 
Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
Duration of Treatment (days) 
 
 
 
n 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) A subject’s compliance rate during the study is 100% * (total number of capsules dispensed minus the total 
number of capsules returned) divided by twice the subject’s duration of treatment. 
 
Source: Listing 16.2.4.1 
 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.2.1 
Time to Event (months) 
ITT Population 
 
Parameter 
Statistic  
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Overall Survival (OS) 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Value of KM at Median Duration (%) 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
 
 
 
 
Covariate= Baseline AFP 
 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
 
 
 
 
 
Covariate= Baseline WBC A3AR 
 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
Time To Progression (TTP) 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Value of KM at Median Duration (%) 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
Progression-free Survival (PFS) 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Value of KM at Median Duration (%) 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
P-value (LR) =P-value using the logrank test. KM=Kaplan-Meier 
Baseline=Cycle 1 Day 1 
Percentages are calculated using the number of subjects in the ITT Population for each treatment as the denominator. 
For Median Duration, see Table 14.1.7. 
HR=Hazard Ratio for Treatment from Proportional Hazards Model with Treatment and the specified covariate in the model 
and P-value (PH) is the corresponding p-value (Chi-Square). 
Source: Listing 16.2.5.1 
 
 


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Statistical Analysis Plan Tables and Listings 
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Figure 14.2.1  
Kaplan-Meier curve for OS 
ITT Population 
 
 
 
Source: Listing 16.2.5.1 
 
 
Figure 14.2.2  
With Number of Subjects at Risk
Product-Limit Survival Estimates
40
15
7
2
1
0
21
6
3
2
1
0
CF102
Placebo
0
5
10
15
20
25
Overall Survival (Month)
0.0
0.2
0.4
0.6
0.8
1.0
Survival Probability
Placebo
CF102
Actual Treatment
0
5
10
15
20
25
Overall Survival (Month)
0.0
0.2
0.4
0.6
0.8
1.0
Survival Probability
Placebo
CF102
Actual Treatment
Logrank p=0.9161


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Kaplan-Meier curve for TTP 
ITT Population 
 
 
Source: Listing 16.2.5.1 
Programming Note: Include number of patients at any month in the figure. 
 
 
With Number of Subjects at Risk
Product-Limit Survival Estimates
31
8
2
0
14
1
1
1
1
1
1
0
CF102
Placebo
0
5
10
15
20
25
30
35
Time to Progression (Month)
0.0
0.2
0.4
0.6
0.8
1.0
Survival Probability
Placebo
CF102
Actual Treatment
0
5
10
15
20
25
30
35
Time to Progression (Month)
0.0
0.2
0.4
0.6
0.8
1.0
Survival Probability
Placebo
CF102
Actual Treatment
Logrank p=0.3574


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Statistical Analysis Plan Tables and Listings 
Page 24 of 109   
 
 
 
 
 
 
 
Figure 14.2.3  
Kaplan-Meier curve for PFS 
ITT Population 
 
 
 
Source: Listing 16.2.5.1 
Programming Note: Include number of patients at any month in the figure. 
 
 
With Number of Subjects at Risk
Product-Limit Survival Estimates
47
11
4
0
25
2
1
1
1
1
1
0
CF102
Placebo
0
5
10
15
20
25
30
35
Progression free Survival (Month)
0.0
0.2
0.4
0.6
0.8
1.0
Survival Probability
Placebo
CF102
Actual Treatment
0
5
10
15
20
25
30
35
Progression free Survival (Month)
0.0
0.2
0.4
0.6
0.8
1.0
Survival Probability
Placebo
CF102
Actual Treatment
Logrank p=0.2682


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Statistical Analysis Plan Tables and Listings 
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Table 14.2.2.1.1 
Overall Response Using RECIST Criteria 
ITT Population 
 
Visit 
Response, n (%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Cycle 3 Day 1 
CR  
xx (xx.x) 
xx (xx.x) 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
 
 
 
 
 
ORR 
xx (xx.x) 
xx (xx.x) 
 
P-value  
0.xxxx 
 
 
DCR 
xx (xx.x) 
xx (xx.x) 
 
P-value  
0.xxxx 
 
Cycle 5 Day 1 
CR  
xx (xx.x) 
xx (xx.x) 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
 
 
 
 
 
ORR 
xx (xx.x) 
xx (xx.x) 
 
P-value  
0.xxxx 
 
 
DCR 
xx (xx.x) 
xx (xx.x) 
 
P-value  
0.xxxx 
 
 
 
 
 
Includes only assessments through Cycle 11. 
CR=Complete Response, PR =Partial Response, SD =Stable Disease, PD=Progressive Disease 
ORR=Objective Response Rate= proportion of subjects who have response of CR or PR  
DCR=Disease Control Rate= proportion of subjects who have response of CR, PR, or SD  
Percentages are calculated using the number of subjects in the ITT Population for each treatment as the denominator. 
P-values determined using the normal approximation to the binomial distribution using observed responses. 
ITT= Intent-to-Treat 
NA = Not Applicable 
Source: Listing 16.2.6.3.1 
 
Programming Notes: Continue for all cycles through Cycle 11.  
Use same structure for Table 14.2.2.1.2 (PP Population) with PP instead of ITT in the two appropriate footnotes 
and the last footnote changed to “Source: Listings 16.2.6.3.1, 16.2.1.2”. 
 
 
 


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Table 14.2.2.2.1 
Best Overall Response  
ITT Population 
 
Best Overall Response, n (%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
CR  
xx (xx.x) 
xx (xx.x) 
PR 
xx (xx.x) 
xx (xx.x) 
SD 
xx (xx.x) 
xx (xx.x) 
PD 
xx (xx.x) 
xx (xx.x) 
Total 
xx 
xx 
 
 
 
ORR 
xx (xx.x) 
xx (xx.x) 
P-value  
0.xxxx 
 
DCR 
xx (xx.x) 
xx (xx.x) 
P-value  
0.xxxx 
 
 
 
 
CR=Complete Response, PR =Partial Response, SD =Stable Disease, PD=Progressive Disease  
ORR=Objective Response Rate= proportion of subjects who have response of CR or PR  
DCR=Disease Control Rate= proportion of subjects who have response of CR, PR, or SD  
Percentages are calculated using the number of subjects in the ITT Population for each treatment as the denominator. 
P-values determined using the normal approximation to the binomial distribution using observed responses. 
Best Overall Response is determined for the entire duration of the study and is counted once per subject, although it 
may occur more than once. 
ITT= Intent-to-Treat 
NA = Not Applicable 
Source: Listing 16.2.6.3.1 
 
Programming Notes: Best Overall Response is determined for the entire duration of the study.  
Use same structure for Table 14.2.2.2.2 (PP Population) with PP instead of ITT in the two appropriate footnotes 
and the last footnote changed to “Source: Listings 16.2.6.3.1, 16.2.1.2”. 
 
 


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Table 14.2.3.1 
WBC A3AR expression 
ITT Population 
 
Visit 
Statistic 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Baseline 
n 
xx 
xx 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
Median 
xxx.x 
xxx.x 
 
Min, Max 
xxx, xxx 
xxx, xxx 
Cycle 3 Day 1 
n 
xx 
xx 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
Median 
xxx.x 
xxx.x 
 
Min, Max 
xxx, xxx 
xxx, xxx 
CFB at Cycle 3 Day 1 
n 
xx 
xx 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
Median 
xxx.x 
xxx.x 
 
Min, Max 
xxx, xxx 
xxx, xxx 
Cycle 5 Day 1 
n 
xx 
xx 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
Median 
xxx.x 
xxx.x 
 
Min, Max 
xxx, xxx 
xxx, xxx 
CFB at Cycle 5 Day 1 
n 
xx 
xx 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
Median 
xxx.x 
xxx.x 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
 
 
 
 
 
 
 
CFB=Change from Baseline 
Baseline=Cycle 1 Day 1 
Missing data for intermediate visits are imputed using LOCF. 
 
Source: Listing 16.2.6.4 
 
 
Programming Note: Continue for all visits (Day 1 for each odd-numbered cycle through Cycle 11), including CFB. 
 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.2.3.2 
 WBC A3AR expression at Baseline by Overall Response 
ITT Population 
 
Visit 
Overall Response 
Statistic 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Cycle 3 Day 1  
CR 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
PR 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
SD 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
PD 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
 
 
 
 
CFB at Cycle 3 Day 1 
CR 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
PR 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
SD 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
PD 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
 
 
 
 
Baseline=Cycle 1 Day 1 
Missing data for intermediate visits are imputed using LOCF. 
 
Source: Listings 16.2.6.3.1, 16.2.6.4 
 
Programming Note: Continue for all visits (Day 1 for each odd-numbered cycle through Cycle 11), including CFB. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
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Table 14.2.3.3 
Overall Response by CFB for WBC A3AR expression  
ITT Population 
 
Visit 
CFB for WBC A3AR 
expression 
Overall Response (n, %) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Cycle 3 Day 1 
< xxx.x (M) 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
 
>= xxx.x (M) 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
Cycle 5 Day 1 
< xxx.x (M) 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
 
>= xxx.x (M) 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFB=Change from Baseline 
Baseline=Cycle 1 Day 1 
Percentages are calculated using the number of subjects in the ITT Population for each treatment as the denominator. 
M=pooled median of CFB for WBC A3AR expression at the specified visit 
Missing data for intermediate visits are imputed using LOCF. 
 
Source: Listings 16.2.6.3.1, 16.2.6.4 
 
Programming Notes: Continue for all visits (Day 1 for each odd-numbered cycle through Cycle 11).  
Specify the value of the median M (xxx.x) at each visit, followed by “(M)”.  
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
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Table 14.2.4.1 
Alpha-fetoproterin (AFP)  
ITT Population 
 
Visit 
Statistic 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Cycle 1 Day 1  
n 
xx 
xx 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
Median 
xxx.x 
xxx.x 
 
Min, Max 
xxx, xxx 
xxx, xxx 
Cycle 2 Day 1 
n 
xx 
xx 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
Median 
xxx.x 
xxx.x 
 
Min, Max 
xxx, xxx 
xxx, xxx 
CFB at Cycle 2 Day 1 
n 
xx 
xx 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
Median 
xxx.x 
xxx.x 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
P-value (1) 
0.xxxx 
 
Cycle 3 Day 1 
n 
xx 
xx 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
Median 
xxx.x 
xxx.x 
 
Min, Max 
xxx, xxx 
xxx, xxx 
CFB at Cycle 3 Day 1 
n 
xx 
xx 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
Median 
xxx.x 
xxx.x 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
P-value (1) 
0.xxxx 
 
 
 
 
 
 
 
 
 
(1) P-value determined using ANCOVA with Baseline and Treatment in the model. 
CFB=Change from Baseline 
Baseline=Cycle 1 Day 1 
Missing data for intermediate visits are imputed using LOCF. 
Source: Listing 16.2.6.4 
 
Programming Notes: Continue for all visits (Day 1 of each cycle through Cycle 11), including CFB.  
P-values are included with each CFB. AFP is collected with lab data.  
Exclude any data for days other than Day 1. 
 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 31 of 109   
 
 
 
 
 
 
 
 
Table 14.2.4.2 
Alpha-fetoproterin (AFP) by Overall Response 
ITT Population 
 
Visit  
Overall Response 
Statistic 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Cycle 3 Day 1  
CR 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
PR 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
SD 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
PD 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
 
 
 
 
 
 
 
 
 
CFB at Cycle 3 Day 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 5 Day 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFB=Change from Baseline 
Baseline=Cycle 1 Day 1 
Missing data for intermediate visits are imputed using LOCF. 
 
Source: Listings 16.2.6.3.1, 16.2.6.4 
 
Programming Notes: Continue for all visits (Day 1 for each odd-numbered cycle through Cycle 11), including CFB. 
 AFP is collected with lab data. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
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Table 14.2.4.3 
Overall Response by Categorical Alpha-fetoproterin (AFP) 
ITT Population 
 
Visit 
AFP (ng/mL) 
Overall Response (n, %) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Cycle 3 Day 1 
<20 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
 
20-200 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
 
>200 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
 
 
 
 
 
Cycle 5 Day 1 
<20 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
 
20-200 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
 
>200 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
Percentages are calculated using the number of subjects in the ITT Population in each category defined 
by AFP for each treatment as the denominator. 
Missing data for intermediate visits are imputed using LOCF. 
 
Source: Listings 16.2.6.3.1, 16.2.6.4 
Programming Notes: Continue for all visits (Day 1 for each odd-numbered cycle).  
AFP is collected with lab data. 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
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Table 14.2.4.4 
Overall Response by CFB for Alpha-fetoproterin (AFP) 
ITT Population 
 
Visit 
CFB for AFP 
Overall Response (n, %) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Cycle 3  Day 1 
<xxx.x (M) 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
 
>= xxx.x (M) 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
Cycle 5 Day 1 
< xxx.x (M) 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
 
>= xxx.x (M) 
CR 
xx (xx.x) 
xx (xx.x) 
 
 
PR 
xx (xx.x) 
xx (xx.x) 
 
 
SD 
xx (xx.x) 
xx (xx.x) 
 
 
PD 
xx (xx.x) 
xx (xx.x) 
 
 
Total 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFB=Change from Baseline 
Baseline=Cycle 1 Day 1  
M=pooled median of CFB for AFP at the specified visit 
Percentages are calculated using the number of subjects in the ITT Population in each category defined by 
AFP for each treatment as the denominator.  
Missing data for intermediate visits are imputed using LOCF. 
 
Source: Listings 16.2.6.3.1, 16.2.6.4 
 
Programming Notes: Continue for all visits (Day 1 for all odd-numbered cycles through Cycle 11). 
Specify the value of the median M (xxx.x) at each visit, followed by “(M)”. AFP is collected with lab data. 
 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
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Table 14.2.5.1 
Alanine aminotransferase (ALT)  
ITT Population 
 
 
Visit 
 
 Statistic 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Pre-Study 
n 
xx 
xx 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
Median 
xxx.xx 
xxx.xxx 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
Cycle 1 Day 1  
n 
xx 
xx 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
Median 
xxx.xx 
xxx.xxx 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
Cycle 1 Day 8 
n 
xx 
xx 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
Median 
xxx.xx 
xxx.xxx 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
CFB to Cycle 1 Day 8 
n 
xx 
xx 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
Median 
xxx.xx 
xxx.xxx 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
P-value (1) 
0.xxxx 
 
Cycle 1 Day 15 
n 
xx 
xx 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
Median 
xxx.xx 
xxx.xxx 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
CFB to Cycle 1 Day 15 
n 
xx 
xx 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
Median 
xxx.xx 
xxx.xxx 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
P-value (1) 
0.xxxx 
 
(1) P-value determined using ANCOVA with Baseline and Treatment in the model. 
CFB=Change From Baseline 
Baseline=Cycle 1 Day 1 (or Pre-Study if <= 3 days prior to Cycle 1 Day 1 or if value at Cycle 1 Day 1 is missing ) 
Missing data for intermediate visits are imputed using LOCF. 
Source: Listing 16.2.8.2   
 
Programming Notes: Continue for remaining visits (Days 1 and 15 through Cycle 11), including CFB. P-values 
are included with each CFB. The following tables will use the above format: Table 14.2.5.2: Aspartate 
aminotransferase (AST), Table 14.2.5.3: Albumin, Table 14.2.5.4: Bilirubin (direct), Table 14.2.5.5: Bilirubin 
(total), Table 14.2.5.6: Prothrombin time (PT) with Source Listing 16.2.8.3, and Table 14.2.5.7: International 
Normalized Ratio (INR) with Source Listing 16.2.8.3 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 35 of 109   
 
 
 
 
 
 
Table 14.2.6 
Hepatitis Viral Load  
ITT Population 
 
Parameter 
Visit 
Statistic  
CF102  
(N=xx) 
Placebo 
 (N=xx) 
log(HBV Load) 
Cycle 1 Day 1 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
Cycle 3 Day 1 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
CFB to Cycle 3 Day 1 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
 
P-value (1) 
0.xxxx 
 
log(HCV Load) 
Cycle 1 Day 1 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
Cycle 3 Day 1 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
CFB to Cycle 3 Day 1 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
 
P-value (1) 
0.xxxx 
 
 
 
 
 
 
(1) P-value determined using ANCOVA with Baseline and Treatment in the model. 
Includes only subjects with positive serology at Screening (Listing 16.2.3.3.1) 
HBV =Hepatitis B Viral; HCV =Hepatitis C Viral.  
log (Value) is the base 10 logarithm of the value. 
CFB= Change From Baseline  
Baseline=Cycle 1 Day 1 
Missing data for intermediate visits are imputed using LOCF. 
Source: Listings 16.2.3.3.1, 16.2.6.5.1, 16.2.6.5.2 
 
Programming Notes: Include only subjects with positive serology at Screening; other subjects should not have data recorded. 
If subjects without positive serology have viral load recorded, include the values in Listings 16.2.6.5.1 and 16.2.6.5.2, but not in the table. 
Continue for all visits (Day 1 of odd-numbered cycles through Cycle 11), including CFB. P-values are included with each CFB. 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 36 of 109   
 
 
 
 
 
 
Table 14.2.7.1 
 Overall Survival (OS; months) by Child-Pugh (CP) Score at Screening 
ITT Population 
 
CP Score 
Statistic  
CF102  
(N=xx) 
Placebo 
 (N=xx) 
CP= 7 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
CP=8 
n 
xx 
xx 
 
 
 
 
 
 
 
 
CP=7 or 8 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
CP=9 
n 
xx 
0 
 
25th Percentile 
xx.x 
 
 
Median 
xx.x 
 
 
75th Percentile 
xx.x 
 
 
Number (%) observed  events  
xx (xx.x) 
 
 
Number (%)  censored  
xx (xx.x) 
 
 
 
 
 
P-value (LR) =P-value using the logrank test.  
Percentages are calculated using the number of subjects in the ITT Population in the specified subgroup category 
for each treatment as the denominator. 
HR=Hazard Ratio for Treatment from Proportional Hazards Model with Treatment as the only factor in the model 
and P-value (PH) is the corresponding p-value (Chi-Square). 
Source: Listings 16.2.3.1, 16.2.5.1 
 
Programming Notes: Continue for CP=8. 
For CP=9, do not include P-value (LR), HR, 95% CI for HR, and P-value (PH) and only enter 0 for ‘n’ for Placebo. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 37 of 109   
 
 
 
 
 
 
Figure 14.2.7.1  
Kaplan-Meier curve for OS  
CP Score at Screening = 7 
ITT Population 
 
 
Source: Listings 16.2.3.1, 16.2.5.1 
 
Programming Note: Use same structure for Figures 14.2.7.2 (OS, CP=8) and 14.2.7.3 (OS, CP= 7 or 8).  
 
 
 
 
With Number of Subjects at Risk
Product-Limit Survival Estimates
40
15
7
2
1
0
21
6
3
2
1
0
CF102
Placebo
0
5
10
15
20
25
Overall Survival (Month)
0.0
0.2
0.4
0.6
0.8
1.0
Survival Probability
Placebo
CF102
Actual Treatment
0
5
10
15
20
25
Overall Survival (Month)
0.0
0.2
0.4
0.6
0.8
1.0
Survival Probability
Placebo
CF102
Actual Treatment
Logrank p=0.9161


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 38 of 109   
 
 
 
 
 
 
 
Table 14.2.7.2 
Overall Survival (OS; months) by Sex 
ITT Population 
 
Sex 
Statistic  
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Male 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
Female 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
P-value (LR) =P-value using the logrank test.  
Percentages are calculated using the number of subjects in the ITT Population in the specified subgroup category 
for each treatment as the denominator. 
HR=Hazard Ratio for Treatment from Proportional Hazards Model with Treatment as the only factor in the model 
and P-value (PH) is the corresponding p-value (Chi-Square). 
Source: Listings 16.2.3.1, 16.2.5.1 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 39 of 109   
 
 
 
 
 
 
Table 14.2.7.3 
Overall Survival (OS; months) by ECOG PS at Baseline 
ITT Population 
 
ECOG PS 
Statistic  
CF102  
(N=xx) 
Placebo 
 (N=xx) 
0 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
1 or 2 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
 
 
 
 
 
 
 
 
P-value (LR) =P-value using the logrank test.  
Percentages are calculated using the number of subjects in the ITT Population in the specified subgroup 
category for each treatment as the denominator. 
HR=Hazard Ratio for Treatment from Proportional Hazards Model with Treatment as the only factor in the 
model and P-value (PH) is the corresponding p-value (Chi-Square). 
Source: Listings 16.2.9.3, 16.2.5.1 
 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 40 of 109   
 
 
 
 
 
 
 
Table 14.2.7.4 
Overall Survival (OS; months) by Alpha-fetoprotein (AFP) at Baseline 
ITT Population 
 
AFP 
Statistic  
CF102  
(N=xx) 
Placebo 
 (N=xx) 
<=400 ng/mL  
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
>400 ng/mL 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
P-value (LR) =P-value using the logrank test.  
Percentages are calculated using the number of subjects in the ITT Population in the specified subgroup 
category for each treatment as the denominator. 
HR=Hazard Ratio for Treatment from Proportional Hazards Model with Treatment as the only factor in the model 
and P-value (PH) is the corresponding p-value (Chi-Square). 
Source: Listings 16.2.6.4, 16.2.5.1 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.2.7.5 
Overall Survival (OS; months) by Prior Locoregional Therapy 
ITT Population 
 
Prior Locoregional Therapy 
Statistic  
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Yes 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
No 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
Locoregional Therapy = HCC Prior Therapies of Radiation or Chemoembolization 
P-value (LR) =P-value using the logrank test.  
Percentages are calculated using the number of subjects in the ITT Population in the specified subgroup category for 
each treatment as the denominator. 
HR=Hazard Ratio for Treatment from Proportional Hazards Model with Treatment as the only factor in the model and 
P-value (PH) is the corresponding p-value (Chi-Square). 
Source: Listings 16.2.3.4, 16.2.5.1 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.2.7.6 
Overall Survival (OS; months) by EHS, PVT, and Either EHS or PVT   
ITT Population 
 
Parameter 
Response 
Statistic  
CF102  
(N=xx) 
Placebo 
 (N=xx) 
EHS 
Yes 
n 
xx 
xx 
 
 
25th Percentile 
xx.x 
xx.x 
 
 
Median 
xx.x 
xx.x 
 
 
75th Percentile 
xx.x 
xx.x 
 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
 
P-value (LR) 
0.xxx 
 
 
 
HR 
x.xx 
 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
 
P-value (PH) 
0.xxx 
 
 
No 
n 
xx 
xx 
 
 
25th Percentile 
xx.x 
xx.x 
 
 
Median 
xx.x 
xx.x 
 
 
75th Percentile 
xx.x 
xx.x 
 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
 
P-value (LR) 
0.xxx 
 
 
 
HR 
x.xx 
 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
 
P-value (PH) 
0.xxx 
 
PVT 
Yes 
n 
xx 
xx 
 
 
25th Percentile 
xx.x 
xx.x 
Either EHS or PVT   
Yes 
n 
xx 
xx 
 
 
25th Percentile 
xx.x 
xx.x 
 
 
 
 
 
EHS= Extrahepatic Spread; PVT=  Portal Vein Thrombosis  
P-value (LR) =P-value using the logrank test.  
Percentages are calculated using the number of subjects in the ITT Population in the specified subgroup category for each 
treatment as the denominator. 
HR=Hazard Ratio for Treatment from Proportional Hazards Model with Treatment as the only factor in the model and P-value 
(PH) is the corresponding p-value (Chi-Square). 
Source: Listings 16.2.3.3.2, 16.2.5.1 
 
 
Programming Note: Continue PVT= Yes and Either EHS or PVT= Yes, and add PVT= No and Either EHS or PVT= No. 
 
 
 


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Statistical Analysis Plan Tables and Listings 
Page 43 of 109   
 
 
 
 
 
 
Table 14.2.7.7 
Overall Survival (OS; months) by History of HBV 
ITT Population 
 
History of HBV 
Statistic  
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Yes 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
No 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
HBV =Hepatitis B Virus 
P-value (LR) =P-value using the logrank test.  
Percentages calculated using the number of subjects in the ITT Population in the specified subgroup category as 
the denominator. 
HR=Hazard Ratio for Treatment from Proportional Hazards Model with Treatment as the only factor in the model 
and P-value (PH) is the corresponding p-value (Chi-Square). 
Source: Listings 16.2.3.3.1, 16.2.5.1 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.2.7.8 
Overall Survival (OS; months) by History of HCV 
ITT Population 
 
History of HCV 
Statistic  
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Yes 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
No 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
HCV =Hepatitis C Virus 
P-value (LR) =P-value using the logrank test.  
Percentages calculated using the number of subjects in the ITT Population in the specified subgroup category as 
the denominator. 
HR=Hazard Ratio for Treatment from Proportional Hazards Model with Treatment as the only factor in the model 
and P-value (PH) is the corresponding p-value (Chi-Square). 
Source: Listings 16.2.3.3.1, 16.2.5.1 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.2.7.9 
Overall Survival (OS; months) by Diagnostic Procedure 
ITT Population 
 
Diagnostic Procedure 
Statistic  
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Cytology/histology 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
AASLD 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
Diagnostic Procedure= Cytology/histology or American Association for the Study of Liver Diseases (AASLD) 
P-value (LR) =P-value using the logrank test.  
Percentages are calculated using the number of subjects in the ITT Population in the specified subgroup category 
for each treatment as the denominator. 
HR=Hazard Ratio for Treatment from Proportional Hazards Model with Treatment as the only factor in the model 
and P-value (PH) is the corresponding p-value (Chi-Square). 
Source: Listings 16.2.3.2, 16.2.5.1 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.2.7.10 
Overall Survival (OS; months) by Country 
ITT Population 
 
Country 
Statistic  
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Bulgaria 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
Israel 
n 
xx 
xx 
 
25th Percentile 
xx.x 
xx.x 
 
Median 
xx.x 
xx.x 
 
75th Percentile 
xx.x 
xx.x 
 
Number (%) observed  events  
xx (xx.x) 
xx (xx.x) 
 
Number (%)  censored  
xx (xx.x) 
xx (xx.x) 
 
P-value (LR) 
0.xxx 
 
 
HR 
x.xx 
 
 
95% CI for HR 
(x.xx, x.xx) 
 
 
P-value (PH) 
0.xxx 
 
 
 
 
 
P-value (LR) =P-value using the logrank test.  
Percentages are calculated using the number of subjects in the ITT Population in the specified subgroup category 
for each treatment as the denominator. 
HR=Hazard Ratio for Treatment from Proportional Hazards Model with Treatment as the only factor in the model 
and P-value (PH) is the corresponding p-value (Chi-Square). 
Source: Listings 16.2.1.1, 16.2.5.1 
Programming Note: Continue for each country (Bulgaria, Israel, Romania, Serbia, or United States) alphabetically. 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.3.1 
Incidence of Treatment-Emergent Adverse Events  
Safety Population 
 
MedDRA System Organ Class 
MedDRA Preferred Term, n (%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
 
 
 
 
Any 
Any 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Body as a Whole 
Any 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Fever 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All AEs in this table are treatment emergent.  
Percentages are calculated using the number of subjects in the Safety Population for each treatment as the denominator. 
MedDRA version: 21.0 
Source: Listing 16.2.7 
 
 
Programming Note: Continue for all SOCs and Preferred Terms.  
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.3.2 
Incidence of Treatment-Emergent Adverse Events by Relationship  
Safety Population 
 
 
MedDRA System Organ Class 
 
MedDRA Preferred Term 
Relationship, n (%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
 
 
 
 
 
Any 
Any 
Definitely Related 
xx (xx.x) 
xx (xx.x) 
 
 
Probably Related 
xx (xx.x) 
xx (xx.x) 
 
 
Possibly Related 
xx (xx.x) 
xx (xx.x) 
 
 
Not Related 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Body as a Whole 
Any 
Definitely Related 
xx (xx.x) 
xx (xx.x) 
 
 
Probably Related 
xx (xx.x) 
xx (xx.x) 
 
 
Possibly Related 
xx (xx.x) 
xx (xx.x) 
 
 
Not Related 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Fever 
Definitely Related 
xx (xx.x) 
xx (xx.x) 
 
 
Probably Related 
xx (xx.x) 
xx (xx.x) 
 
 
Possibly Related 
xx (xx.x) 
xx (xx.x) 
 
 
Not Related 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All AEs in this table are treatment emergent.  
Relationship is the most related AE for each MedDRA System Organ Class and Preferred Term for each subject. 
Percentages are calculated using the number of subjects in the Safety Population for each treatment as the denominator.  
MedDRA version: 21.0 
Source: Listing 16.2.7 
 
Programming Notes: Continue for all SOCs and Preferred Terms. Include “Possibly Related” and “Not Related” 
for all SOCs and PTs; include “Definitely Related” and “Probably Related” for SOCs and PTs when such are 
recorded for relationship.  
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.3.3 
Incidence of Treatment Emergent Adverse Events By Severity 
Safety Population 
 
 
MedDRA System Organ Class 
 
MedDRA Preferred Term 
Severity, n (%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
 
 
 
 
 
Any 
Any 
Mild 
xxx (xx.x) 
xxx (xx.x) 
 
 
Moderate 
xxx (xx.x) 
xxx (xx.x) 
 
 
Severe 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
Body as a Whole 
Any 
Mild 
xxx (xx.x) 
xxx (xx.x) 
 
 
Moderate 
xxx (xx.x) 
xxx (xx.x) 
 
 
Severe 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
Fever 
Mild 
xxx (xx.x) 
xxx (xx.x) 
 
 
Moderate 
xxx (xx.x) 
xxx (xx.x) 
 
 
Severe 
xxx (xx.x) 
xxx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All AEs in this table are treatment emergent.  
Severity is the most severe AE, i.e. largest severity grade, for each MedDRA System Organ Class and Preferred Term for each subject. 
Percentages are calculated using the number of subjects in the Safety Population for each treatment as the denominator. 
MedDRA version: 21.0 
Source: Listing 16.2.7 
 
 
Programming Notes: Continue for all SOCs and Preferred Terms.AE severity is recorded using grade.  
Display as Mild, Moderate, Severe, Life-Threatening, or Fatal for Grade 1, Grade 2, Grade 3, Grade 4, 
or Grade 5, respectively. Include Mild or Moderate for all SOCs and PTs and include Severe, Life-
Threatening, or Fatal only for those SOCs and PTs when such are recorded for severity (i.e. with 
severity of Grades 3, 4 or 5, respectively).  
 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.3.4.1 
Listing of Deaths 
Safety Population 
 
Site/ 
Subject 
Treatment 
Last Visit 
Date of 
Final Dose 
Date of Death 
Primary Cause 
of Death 
Autopsy 
Performed? 
Date of Autopsy 
 
 
 
 
 
 
 
 
xxx/xxxx 
xxxxxxxx 
xx 
DD/MM/YY 
DD/MM/YY 
xxxxxxxxxxxxx 
xxxx 
DD/MM/YY 
xxx/xxxx 
xxxxxxxx 
xx 
DD/MM/YY 
DD/MM/YY 
xxxxxxxxxxxxx 
xxxx 
DD/MM/YY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes subjects who discontinued from dosing or discontinued from the study for termination reason of death.  
All deaths are given in Listing 16.2.5.1. 
Source: Listings 16.2.1.1, 16.2.5.1, 16.2.7 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.3.4.2 
Listing of Serious Adverse Events 
Safety Population 
 
Site/ 
Subject 
Treatment 
System Organ Class / 
Preferred Term/ 
Verbatim Term 
Start  
Date 
Stop  
Date (1) 
Relative 
Start Day 
Relative 
Stop Day 
Severity 
(2) 
Freq. 
(3) 
Relation 
(4) 
Action 
Taken 
(5) 
Outcome 
(6) 
Serious? 
xxx/xxxx 
xxxxx 
xxxxxx / 
  xxxxxx/  
    xxxxxxx 
DD/MM/YY DD/MM/YY 
xx 
xx 
x 
x 
x 
x 
x 
 
 x 
xxx/xxxx 
xxxxx 
xxxxxx / 
  xxxxxx/  
    xxxxxxx 
DD/MM/YY DD/MM/YY 
xx 
xx 
x 
x 
x 
x 
x 
 
 x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relative Start / Stop Dates = Days from Baseline to Start / Stop 
(1) O=AE ongoing 
(2) Severity: 1= Mild,  2= Moderate, 3= Severe but not immediately life-threatening, 4= Life-threatening consequences, 5=Death 
(3) Frequency: 1= Single episode 2= Intermittent 3= Continuous 
(4) Relationship: 1= Definitely related 2= Probably related 3= Possibly related 4= Not related 
(5) Action Taken: 0= None 1= Medication TX 2= Non-medication TX 3= Hospitalization 4= Study drug delayed, 5= Study drug discontinued 
(6) Outcome: 1= Resolved 2= Resolved with sequelae 3= Unresolved 4= Death 
MedDRA version: 21.0 
 
Source: Listing 16.2.7 
 
 
Programming Note: Sort by site, subject and start date.  
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
Page 52 of 109   
 
 
 
 
 
 
 
 
Table 14.3.5 
Listing of Discontinuations Due to Adverse Events 
Safety Population 
 
Site/ 
Subject 
Treatment 
Date of 
Final Dose 
 
Date of Withdrawal from Trial 
or Dosing  
 
Primary Reason 
 
Specify 
xxx/xxxx 
xxxxxxxx 
DD/MM/YY 
DD/MM/YY 
xxxxxxxxxxxxxxxxxxxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes only subjects with AE recorded as reason for withdrawal from dosing or trial 
Source: Listings 16.2.1.1, 16.2.7 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.3.6.1 
Clinical Laboratory Evaluations: Hematology 
Safety Population 
 
Parameter (Units) 
 
Visit 
 
 Statistic 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
XXXXXXXXX 
Pre-Study 
n 
xx 
xx 
(UNITS) 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
Cycle 1 Day 1 
n 
xxx 
xxx 
 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
Cycle 1 Day 8 
n 
xxx 
xxx 
 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
CFB to Cycle 1 Day 8 
n 
xxx 
xxx 
 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
 
 
 
 
 
xxxxx 
n 
xxx 
xxx 
 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
CFB to xxxxx 
n 
xxx 
xxx 
 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
 
 
 
 
CFB=Change From Baseline  
Baseline=Cycle 1 Day 1 (or Pre-Study if <= 3 days prior to Cycle 1 Day 1 or if value at Cycle 1 Day 1 is missing) 
Includes visits with at least 4 subjects in either treatment group 
Source: Listing 16.2.8.1 
 
Programming Notes: Continue for all parameters and all visits (Days 1, 8, and 15 for Cycle 1, and Days 1 and 15 for subsequent cycles), 
including CFB. Include visits with at least 4 subjects in either treatment group. The following tables will use the above format:  
Table 14.3.6.2 Clinical Laboratory Evaluations: Blood Chemistry (Safety Population) with Source: Listing 16.2.8.2 and 
Table 14.3.6.3 Clinical Laboratory Evaluations: Coagulation (Safety Population) with Source: Listing 16.2.8.3. 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.3.6.4 
Clinical Laboratory Evaluations: Thyroid Function 
Safety Population 
 
Parameter (Units) 
 
Visit 
 
 Statistic 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
T3 (Unit) 
Pre-Study 
n 
xx 
xx 
 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
Cycle 1  
n 
xxx 
xxx 
 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
Cycle 2 
n 
xxx 
xxx 
 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
CFB to Cycle 2 
n 
xxx 
xxx 
 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
 
 
 
 
 
xxxxx 
n 
xxx 
xxx 
 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
CFB to xxxxx 
n 
xxx 
xxx 
 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
 
 
 
 
CFB=Change From Baseline  
Baseline=Cycle 1 (or Pre-Study if <= 3 days prior to Cycle 1 Day 1 or if value at Cycle 1 Day 1 is missing) 
Includes visits with at least 4 subjects in either treatment group 
Source: Listing 16.2.8.5 
 
Programming Note: Continue for T4 (Unit) and TSH (Unit) and all cycles with at least 4 subjects in either treatment group. 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.3.7.1 
 
ECOG Performance Status 
Safety Population 
 
Visit 
ECOG PS, n (%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Pre-Study 
0 
xx (xx.x) 
xx (xx.x) 
 
1 
xx (xx.x) 
xx (xx.x) 
 
2 
xx (xx.x) 
xx (xx.x) 
 
3 
xx (xx.x) 
xx (xx.x) 
 
4 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
Cycle 1 Day 1 
0 
xx (xx.x) 
xx (xx.x) 
 
1 
xx (xx.x) 
xx (xx.x) 
 
2 
xx (xx.x) 
xx (xx.x) 
 
3 
xx (xx.x) 
xx (xx.x) 
 
4 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
Cycle 2 Day 1 
0 
xx (xx.x) 
xx (xx.x) 
 
1 
xx (xx.x) 
xx (xx.x) 
 
2 
xx (xx.x) 
xx (xx.x) 
 
3 
xx (xx.x) 
xx (xx.x) 
 
4 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
Cycle 3 Day 1 
0 
xx (xx.x) 
xx (xx.x) 
 
1 
xx (xx.x) 
xx (xx.x) 
 
2 
xx (xx.x) 
xx (xx.x) 
 
3 
xx (xx.x) 
xx (xx.x) 
 
4 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
0=Normal activity, 1=Symptoms but ambulatory, 2= In bed <50% of time, 3=In bed >50% of time, 4=100% bedridden 
Baseline=Cycle 1 Day 1 (or Pre-Study if <= 3 days prior to Cycle 1 Day 1 or if value at Cycle 1 Day 1 is missing) 
Percentages are calculated using the number of subjects in the Safety Population for each treatment as the denominator.  
Includes visits with at least 4 subjects in either treatment group 
Source: Listing 16.2.9.3 
 
Programming Notes: Continue for all cycles with at least 4 subjects in either treatment group.  
Include ‘4’ only for cycles with a non-zero frequency for at least one treatment. 
 
 


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Statistical Analysis Plan Tables and Listings 
Page 56 of 109   
 
 
 
 
 
 
 
Table 14.3.7.2 
Change from Baseline in ECOG Performance Status 
Safety Population 
 
Visit 
CFB  in  
ECOG PS, n (%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Cycle 2 Day 1 
Decrease 
xx (xx.x) 
xx (xx.x) 
 
No Change 
xx (xx.x) 
xx (xx.x) 
 
Increase 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
 
 
 
 
Cycle 3 Day 1 
Decrease 
xx (xx.x) 
xx (xx.x) 
 
No Change 
xx (xx.x) 
xx (xx.x) 
 
Increase 
xx (xx.x) 
xx (xx.x) 
 
Total 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFB=Change from Baseline 
Baseline=Cycle 1 Day 1 (or Pre-Study if <= 3 days prior to Cycle 1 Day 1 or if value at Cycle 1 Day 1 is missing) 
Percentages are calculated using the number of subjects in the Safety Population for each treatment as the denominator. 
Includes visits with at least 4 subjects in either treatment group 
Source: Listing 16.2.9.3 
 
 
Programming Note: Continue for all visits (Day 1 for all cycles) with at least 4 subjects in either treatment group. 
 
 
 
 


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Table 14.3.8 
Vital Signs And Weight  
Safety Population 
 
Parameter (Units) 
 
Visit 
 
 Statistic 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Systolic BP (mmHg) 
Pre-Study 
n 
xx 
xx 
 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
Baseline 
n 
xx 
xx 
 
 
Mean(SD) 
xxx.xx (xxx.xxx) 
xxx.xx (xxx.xxx) 
 
 
Median 
xxx.xx 
xxx.xxx 
 
 
Min, Max 
xxx.x, xxx.x 
xxx.x, xxx.x 
 
Cycle 1 Day 1  
Hour 1 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
CFB to  
Cycle 1 Day 1 Hour 1 
n 
xx 
xx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BP=Blood Pressure 
BMI=Body mass index 
CFB= Change From Baseline 
Baseline=Cycle 1 Day 1 (or Pre-Study if <= 3 days prior to Cycle 1 Day 1 or if value at Cycle 1 Day 1 is missing) 
Includes visits with at least 4 subjects in either treatment group 
Source: Listings 16.2.9.1, 16,2.9.2 
 
Programming Notes: Continue for Diastolic BP (mmHg), Pulse (beats/min), Temperature (deg C), Respiratory Rate (/min), Weight 
(kg), and BMI (kg/m2) and visits (Days 1 and 15 of each cycle, Day 8 of Cycle 1, and Hours 1, 2, 3, 4, 6 and 8 on Cycle 1 Day 1) with 
CFB. Weight (kg) is not recorded at Hours 1, 2, 3, 4, 6 and 8 on Cycle 1 Day 1. Include visits with at least 4 subjects in either 
treatment group. 
 
 
 


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Table 14.3.9.1 
Electrocardiogram (ECG) Parameters  
Safety Population 
 
Parameter 
Visit 
Statistic  
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Heart Rate (bpm) 
Pre-Study 
n 
xxx 
xxx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
Baseline 
n 
xxx 
xxx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
Cycle 1 Day 1 Hour 2 
n 
xxx 
xxx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
CFB to Cycle 1 Day 1 Hour 2 
n 
xxx 
xxx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
QTcF (msec) (1) 
Pre-Study 
n 
xxx 
xxx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
Baseline 
n 
xxx 
xxx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
Cycle 1 Day 1 Hour 2 
n 
xxx 
xxx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
 
CFB to Cycle 1 Day 1 Hour 2 
n 
xxx 
xxx 
 
 
Mean (SD) 
xxx.x (xxx.xx) 
xxx.x (xxx.xx) 
 
 
Median 
xxx.x 
xxx.x 
 
 
Min, Max 
xxx, xxx 
xxx, xxx 
(1) QTcF= QT Correction- Fridericia 
CFB= Change From Baseline 
Baseline=Cycle 1 Day 1 Hour 0 (or Pre-Study  if value at Cycle 1 Day 1 is missing)  
Includes visits with at least 4 subjects in either treatment group 
Source: Listing 16.2.10.1 
Programming Notes: Continue for QRS Complex (msec), PR Interval (msec), and QTcF (msec) in that order and all visits (pre-Study, 
pre-dose at all visits, and at 2, 4, and 6 hours post-dose on Days 1 and 8 of Cycle 1) with CFB. Compute QTcF=QT*(HR/60)1/3. 
Include visits with at least 4 subjects in either treatment group.  
 


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Table 14.3.9.2 
Categorical Electrocardiogram (ECG) Parameters  
Safety Population 
 
Parameter 
Visit 
Response, n (%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Overall Impression 
Pre-Study 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
 
NCS 
xxx (xx.x) 
xxx (xx.x) 
 
 
CS 
xxx (xx.x) 
xxx (xx.x) 
 
 
Total 
xx 
xx 
 
Baseline 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
 
NCS 
xxx (xx.x) 
xxx (xx.x) 
 
 
CS 
xxx (xx.x) 
xxx (xx.x) 
 
 
Total 
xx 
xx 
 
Cycle 1 Day 1 Hour 2 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
 
NCS 
xxx (xx.x) 
xxx (xx.x) 
 
 
CS 
xxx (xx.x) 
xxx (xx.x) 
 
 
Total 
xx 
xx 
 
Cycle 1 Day 1 Hour 4 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
 
NCS 
xxx (xx.x) 
xxx (xx.x) 
 
 
CS 
xxx (xx.x) 
xxx (xx.x) 
 
 
Total 
xx 
xx 
 
Cycle 1 Day 1 Hour 6 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
 
NCS 
xxx (xx.x) 
xxx (xx.x) 
 
 
CS 
xxx (xx.x) 
xxx (xx.x) 
 
 
Total 
xx 
xx 
 
Cycle 1 Day 8 Pre-Dose 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
 
NCS 
xxx (xx.x) 
xxx (xx.x) 
 
 
CS 
xxx (xx.x) 
xxx (xx.x) 
 
 
Total 
xx 
xx 
 
Cycle 1 Day 8 Hour 2 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
 
NCS 
xxx (xx.x) 
xxx (xx.x) 
 
 
CS 
xxx (xx.x) 
xxx (xx.x) 
 
 
Total 
xx 
xx 
NCS= Abnormal-not clinically significant (NCS) 
CS= Abnormal-clinically significant (CS)  
Baseline=Cycle 1 Day 1 Hour 0  (or Pre-Study if value at Cycle 1 Day 1 is missing) 
Percentages are calculated using the number of subjects in the Safety Population for each treatment as the denominator. 
Includes visits with at least 4 subjects in either treatment group 
Source: Listing 16.2.10.2. 
 
Programming Notes:  Continue for ST Segment and Cardiac Rhythm (Normal, Abnormal, and Total) and all visits (Pre-Study visit, Days 1 
and 15 of all cycles, Day 8 of Cycle 1, and at 2, 4, and 6 hours post-dose on Day 1 of Cycle 1, and at Follow-up). Include visits with at 
least 4 subjects in either treatment group.  
 


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Table 14.3.10.1 
Physical Examination at Pre-Study Visit 
Safety Population 
 
 
Body System 
 
Response, n (%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
General Appearance 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
Abnormal 
xxx (xx.x) 
xxx (xx.x) 
 
Total 
xxx 
xxx 
Head and Neck  
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
Abnormal 
xxx (xx.x) 
xxx (xx.x) 
 
Total 
xxx 
xxx 
Eyes, Ears, Nose, Throat 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
Abnormal 
xxx (xx.x) 
xxx (xx.x) 
 
Total 
xxx 
xxx 
Skin 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
Abnormal 
xxx (xx.x) 
xxx (xx.x) 
 
Total 
xxx 
xxx 
Chest / Lungs / Breast 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
Abnormal 
xxx (xx.x) 
xxx (xx.x) 
 
Total 
xxx 
xxx 
Heart 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
Abnormal 
xxx (xx.x) 
xxx (xx.x) 
 
Total 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
Abnormal 
xxx (xx.x) 
xxx (xx.x) 
 
Total 
xxx 
xxx 
Other (1) 
Normal 
xxx (xx.x) 
xxx (xx.x) 
 
Abnormal 
xxx (xx.x) 
xxx (xx.x) 
 
Total 
xxx 
xxx 
 
 
 
 
 
(1) Subjects with more than one assessment of “Other” are counted once. 
Percentages are calculated using the number of subjects in the Safety Population for each treatment as 
the denominator. 
Abnormalities are provided in the listing. 
Source: Listing 16.2.11 .1 
 
Programming Notes: Include other body systems. Subjects with more than one assessment of “Other” are counted once.  
Do not include “Not Assessed”. 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.3.10.2 
Physical Examination 
Safety Population 
 
 
Visit  
 
Clin. Sig.  
Changes (1), n (%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
Cycle 1 Day 1 
Yes  
xxx (xx.x) 
xxx (xx.x) 
 
No 
xxx (xx.x) 
xxx (xx.x) 
 
Total 
xxx 
xxx 
Cycle 1 Day 8  
Yes  
xxx (xx.x) 
xxx (xx.x) 
 
No 
xxx (xx.x) 
xxx (xx.x) 
 
Total 
xxx 
xxx 
Cycle 1 Day 15  
Yes  
xxx (xx.x) 
xxx (xx.x) 
 
No 
xxx (xx.x) 
xxx (xx.x) 
 
Total 
xxx 
xxx 
Cycle 2 Day 1  
Yes  
xxx (xx.x) 
xxx (xx.x) 
 
No 
xxx (xx.x) 
xxx (xx.x) 
 
Total 
xxx 
xxx 
Cycle 2 Day 15  
Yes  
xxx (xx.x) 
xxx (xx.x) 
 
No 
xxx (xx.x) 
xxx (xx.x) 
 
Total 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
(1) Are there any clinically significant changes from the physical examination conducted at the 
previous assessment? 
Percentages are calculated using the number of subjects in the Safety Population for each 
treatment as the denominator. 
Abnormalities associated with clinically significant changes are provided in the listing. 
Includes visits with at least 4 subjects in either treatment group 
Source: Listing 16.2.11.2   
 
Programming Note: Continue for all visits (Days 1, 8, and 15 of Cycle 1 and Days 1 and 15 of 
subsequent cycles) with at least 4 subjects in either treatment group. 
 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Table 14.3.11 
Prior and Concomitant Medications  
Safety Population 
 
ATC Level 3 Class, n (%) 
CF102  
(N=xx) 
Placebo 
 (N=xx) 
None 
xx (xx.x) 
xx (xx.x) 
Class 1  
xx (xx.x) 
xx (xx.x) 
Class 2 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes medications taken within 30 days prior to Screening Visit. 
Percentages are calculated using the number of subjects in the Safety Population for each treatment 
as the denominator. 
Sum of percentages may exceed 100% because subjects could take Concomitant Medications 
within more than one ATC Level 3 Class. 
Source: Listing 16.2.12 
 
 
Programming Note: Continue for all observed Therapeutic Classes 
Individual medications are not tabulated; only the ATC Level 3 Class. 
Check that no subject has “None” for Complications with another response. 
  
 


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4.2. 
Listing Examples 
 
 
Listing 16.2.1.1 
Completed and Discontinued Subjects with Primary Reason for Withdrawal 
 
Site/ 
Subject 
Country 
Treatment 
Date of 
Final Dose 
Complete 
6 Months? 
Withdrawn 
from dosing 
or from trial? 
Date of Early 
Termination  
Primary Reason for 
Withdrawal from 
Dosing 
Primary Reason 
for Withdrawal 
from Trial 
Specify / 
Comment 
xxx/xxxx 
xxxxxxx 
xxxxxxx 
DD/MM/YY 
No 
Yes 
DD/MM/YY 
xxxxxxxx 
 
 
xxx/xxxx 
xxxxxxx 
xxxxxxx 
DD/MM/YY 
Yes 
Yes 
DD/MM/YY 
 
xxxxxxxx 
 
xxx/xxxx 
xxxxxxx 
xxxxxxx 
DD/MM/YY 
Yes 
No 
 
 
 
 
xxx/xxxx 
xxxxxxx 
xxxxxxx 
DD/MM/YY 
No 
Yes 
DD/MM/YY 
 
xxxxxxxx 
xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Country is based on the first digit of the site number (1=Bulgaria, 2=Serbia, 3=Israel, 5=Romania, or 7=United States). 
Further information regarding deaths is given in Table 14.3.4.1. 
 
Programming Notes: For Primary Reason for Withdrawal from Dosing, use: 
“Grade 3”, “Grade 4”, “> 1 dose reduction”, “Delay > 14 days”, “Withdrawal of consent”, “Withdrawal of subject by Investigator”, “Intercurrent 
illness”, “Pregnancy”, “Noncompliance”, or “Termination of the trial by Sponsor”. 
 
For Primary Reason for Withdrawal from Trial, use: “Withdrawal of consent”, “Termination of the trial by Sponsor”, “Death”, or “Other”. 
The response to “Specify / Comment” is the text description for  
Primary Reason for Withdrawal from Dosing = “Grade 3”, “Grade 4”, or “Withdrawal of subject by Investigator”, or  
Primary Reason for Withdrawal from Trial = ‘Other’, or ‘Comments’ at the end of the “Termination” module. 
 
Subjects should have response to either Primary Reason for Withdrawal from Dosing or Primary Reason for Withdrawal from Trial, but not BOTH. 
Sort listing by site and subject. Present country as Bulgaria, Serbia, Israel, Romania, or United States. 
 
 
 


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Listing 16.2.1.2 
Subjects Excluded from Analysis Populations  
 
Site/ Subject 
Treatment 
Excluded from 
ITT Population? 
Excluded from 
PP Population? 
Reason for Exclusion  
xxx/xxxx 
xxxxxxx 
No 
Yes 
xxxxxxx 
xxx/xxxx 
xxxxxxx 
Yes 
Yes 
xxxxxxx 
 
 
 
 
 
 
 
 
 
 
Includes only subjects excluded from the ITT or PP Population. 
All subjects excluded from the ITT Population are also excluded from the PP Population. 
ITT= Intent-to-Treat 
PP=Per Protocol 
 
Programming Notes: Include only subjects excluded from ITT or PP Population.  
All subjects excluded from the ITT Population are also excluded from the PP Population. 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Listing 16.2.2.1 
Inclusion Criteria 
 
 
Site/ 
Subject 
Treatment 
 
 
Consent Date 
Date of 
Screening 
Visit 
 
 
IN1 
 
 
IN2 
 
 
IN3 
 
 
IN4 
 
 
IN5 
 
 
IN6 
 
 
IN7 
 
 
IN8 
 
 
IN9 
 
 
IN10 
 
 
IN11 
 
 
IN12 
xxx/xxxx 
xxxxx 
DD/MM/YYYY 
DD/MM/YY 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
xxx/xxxx 
xxxxx 
DD/MM/YYYY 
DD/MM/YY 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See last page for list of criteria. 
 
Programming Note: Place the criteria definitions on the last page(s). 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Listing 16.2.2.1 
Inclusion Criteria 
 
Inclusion Criteria Questions 
 
IN1= Males and females at least 18 years of age. 
IN2= Diagnosis of HCC: 
 
For patients without underlying cirrhosis at the time of diagnosis, diagnosis of HCC documented by cytology and/or histology. 
 
For patients with underlying cirrhosis at the time of diagnosis, diagnosis of HCC established according to the American Association for the Study of Liver Diseases Practice 
Guideline algorithm. 
IN3= HCC is advanced, ie, treatment-refractory or metastatic, and no standard therapies are expected to be curative. 
IN4= Receipt of prior sorafenib therapy for at least 3 weeks and withdrawal from treatment due either to: 
a) Intolerability; If treatment was withdrawn due to intolerability manifested as a Grade 3 or 4 event by National Cancer Institute Common Toxicity Criteria for Adverse Events 
(CTCAE v4.0), less than 3 weeks of continuous prior administration prior to withdrawal is acceptable (see also Exclusion Criterion #3). Or; 
b) Radiographic evidence of disease progression. 
IN5= Prior sorafenib treatment was discontinued for at least 2 weeks prior to the Baseline Visit. 
IN6= Eastern Collaborative Oncology Group (ECOG) performance status (PS) of ≤ 2. 
IN7= Cirrhosis classified as Child-Pugh Class B. 
IN8= The following laboratory values must be documented within 3 days prior to the first dose of study drug: 
 
Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L 
 
Platelet count ≥ 75 x 10^9/L 
 
Serum creatinine ≤2.0 mg/dL 
 
Aspartic aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × upper limit of normal (ULN) 
 
Total bilirubin ≤ 3.0 mg/dL. 
 
Serum albumin ≥ 2.8 g/dL. 
 
Prothrombin time (PT) no greater than 6 seconds longer than control. 
IN9= Life expectancy of ≥ 6 weeks. 
IN10= For women of childbearing potential, negative serum pregnancy test result. 
IN11= Provide written informed consent to participate. 
IN12= Willing to comply with scheduled visits, treatment plans, laboratory assessments, and other trial related procedures. 
 
 
 
 
 
 
 


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Statistical Analysis Plan Tables and Listings 
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Listing 16.2.2.2 
Exclusion Criteria 
 
 
Site/ 
Subject 
Treatment 
 
EX1 
 
EX2 
 
EX3 
 
EX4 
 
EX5 
 
EX6 
 
EX7 
 
EX8 
 
EX9 
 
EX10 
 
EX11 
 
EX12 
 
EX13 
 
EX14 
 
EX15 
 
EX16 
 
EX17 
 
EX18 
 
EX19 
xxx/xxxxx 
xxxxx 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
xxx/xxxxx 
xxxxx 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See last page for list of criteria. 
 
 
Programming Note: Place the criteria definitions on the last page(s). 
 
 
 


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Listing 16.2.2.2 
Exclusion Criteria 
  
Exclusion Criteria Questions: 
 
EX1= Receipt of no, or of >1, prior systemic drug therapies for HCC. 
EX2= Any systemic cancer therapy, immunomodulatory drug therapy, immunosuppressive therapy, or corticosteroids > 20 mg/day prednisone or equivalent, within 14 days prior to the 
Baseline Visit or concurrently during the trial. 
EX3= Presence of an acute or chronic toxicity of prior chemotherapy that has not resolved to ≤ Grade 1, as determined by CTCAE v 4.0. 
EX4= Locoregional treatment within 4 weeks prior to the Baseline Visit. 
EX5= Major surgery or radiation therapy within 4 weeks prior to the Baseline Visit. 
EX6= Use of any investigational agent within 4 weeks prior to the Baseline Visit. 
EX7= Child-Pugh Class A or C cirrhosis, or hepatic encephalopathy. 
EX8= Occurrence of esophageal or other gastrointestinal hemorrhage requiring transfusion within 4 weeks prior to the Baseline Visit.  
EX9= Uncontrolled or clinically unstable thyroid disease, per judgment of the Principal Investigator. 
EX10= Active bacterial, viral, or fungal infection requiring systemic therapy or operative or radiological intervention. 
EX11= Known human immunodeficiency virus- or acquired immunodeficiency syndrome-related illness. 
EX12= Liver transplant. 
EX13= Active malignancy other than HCC. 
EX14= Uncontrolled arterial hypertension or congestive heart failure (New York Heart Association Classification 3 or 4). 
EX15= Angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 3 months 
prior to initiation of study drug. 
EX16= History of or ongoing cardiac dysrhythmias requiring treatment, atrial fibrillation of any grade, or persistent prolongation of the QTc (Fridericia) interval to > 450 msec for males 
or > 470 msec for females. 
EX17= Pregnant or lactating female. 
EX18= Women of childbearing potential, unless they agree to use dual contraceptive methods which, in the opinion of the Investigator, are effective and adequate for the subject’s 
circumstances while on study drug. 
EX19= Men who partner with a woman of childbearing potential, unless they agree to use effective, dual contraceptive methods (i.e., a condom, with female partner using oral, 
injectable, or barrier method) while on study drug and for 3 months afterward. 
EX20= Any severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug 
administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with the interpretation of study 
results and, in the investigator’s opinion, would make the subject inappropriate for entry into this study. 
 
  
 
 
 
 
 
 
 


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Listing 16.2.3.1 
Demographic and Baseline Characteristics 
 
 
Site/ Subject 
Treatment 
 
Age 
 
Date of Birth 
 
Origin 
 
Sex 
CP Score (1) 
xxx/xxxx 
xxxxx 
xx 
DD/MM/YY 
xxxxx 
xxxxx 
x 
xxx/xxxx 
xxxxx 
xx 
DD/MM/YY 
xxxxx 
xxxxx 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) CP Score= Child- Pugh Score at Screening 
 
 
Programming Note: Compute Age as (the number of days from Date of Birth to Date of Screening Visit)/365.25 
 
 
 


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Listing 16.2.3.2 
HCC Diagnosis   
 
 
Site/ Subject 
Treatment 
Diagnosis Date 
 
Most recent relapse 
and/or re-staging date 
 
Diagnosis 
Established by (1) 
If Diagnosis Established by 
Cytology/histology, specify 
histopathological diagnosis 
xxx/xxxx 
xxxxx 
DD/MM/YY 
DD/MM/YY 
xxxxxx 
xxxxxxxxxxxx 
xxx/xxxx 
xxxxx 
DD/MM/YY 
DD/MM/YY 
xxxxxx 
 
xxx/xxxx 
xxxxx 
DD/MM/YY 
DD/MM/YY 
xxxxxx 
xxxxxxxxxxxx 
 
 
 
 
 
 
 
(1) AASLD=American Association for the Study of Liver Diseases 
 
 
Programming Note:  If diagnosis was established by American Association for the Study of Liver Diseases, present as AASLD.  
 
 
 


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Listing 16.2.3.3.1 
HCC History  
 
 
Site/ 
Subject 
Treatment 
Date of 
Screening 
Visit 
 
Known History 
of Viral 
Hepatitis?  
Date of 
Diagnosis of 
Hepatitis B 
Date of 
Diagnosis of 
Hepatitis C 
Hepatitis B 
Virus 
Serology 
Date of Last 
Hepatitis B 
Testing 
Hepatitis C 
Virus 
Serology 
Date of Last 
Hepatitis C 
Testing 
Complications (1) 
xxx/xxxx 
xxxxx 
DD/MM/YY 
Yes 
DD/MM/YY 
DD/MM/YY 
xxxxxxxxxxx 
DD/MM/YY 
xxxxxxxxxxx 
DD/MM/YY 
xxxxx 
xxx/xxxx 
xxxxx 
DD/MM/YY 
No 
 
 
xxxxxxxxxxx 
DD/MM/YY 
xxxxxxxxxxx 
DD/MM/YY 
xxxxx 
xxx/xxxx 
xxxxx 
DD/MM/YY 
Yes 
DD/MM/YY 
DD/MM/YY 
xxxxxxxxxxx 
 
xxxxxxxxxxx 
DD/MM/YY 
xxxxx 
xxx/xxxx 
xxxxx 
DD/MM/YY 
Yes 
DD/MM/YY 
 
xxxxxxxxxxx 
DD/MM/YY 
xxxxxxxxxxx 
DD/MM/YY 
xxxxx 
 
 
 
 
 
 
 
 
 
 
xxxxx 
xxx/xxxx 
xxxxx 
DD/MM/YY 
Yes 
DD/MM/YY 
DD/MM/YY 
xxxxxxxxxxx 
DD/MM/YY 
xxxxxxxxxxx 
DD/MM/YY 
None 
xxx/xxxx 
xxxxx 
DD/MM/YY 
Yes 
 
DD/MM/YY 
xxxxxxxxxxx 
DD/MM/YY 
xxxxxxxxxxx 
DD/MM/YY 
xxxxx 
 
 
 
 
 
 
 
 
 
 
 
(1) Known complication(s) of cirrhosis and/or portal hypertension 
 
Programming Notes: If date of last testing is missing, then the field should be blank. “Serology” should not be blank. If none of the specified 
responses, including Other, are selected for Complications, then the response should be reported as “None”. If “Other, specify” is reported for 
complication, then report the specified details as the complication. If more than 1 complication is reported, then multiple lines per subject should 
be used. Date of Screening Visit must match that given in Listing 16.2.2.1.  
 
 
 


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Listing 16.2.3.3.2 
Extrahepatic Spread (EHS) and Portal Vein Thrombosis (PVT) 
 
Site/ Subject 
Treatment 
EHS 
PVT 
Either EHS 
or PVT 
Both EHS 
and PVT 
xxx/xxxx 
xxxxx 
xxx 
xxx 
xxx 
xx 
xxx/xxxx 
xxxxx 
xxx 
xxx 
xxx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EHS = Extrahepatic Spread, PVT = Portal Vein Thrombosis 
 
 
Programming Notes: Record each response as “Yes”, “No”, or “Unknown”.  
Include only subjects with one of these responses recorded. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 73 of 109   
 
 
 
 
 
 
 
Listing 16.2.3.4 
HCC Prior Therapies 
 
 
Site/ Subject 
 
 
Treatment 
Modality 
Code (1) 
Modality Details 
Intent (2) 
Best 
response to 
treatment 
If Intent=”Other”, 
Specify 
 
 
Start Date 
 
 
Stop Date 
xxx/xxxx 
xxxxx 
xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
 
DD/MM/YY 
DD/MM/YY 
xxx/xxxx 
xxxxx 
xx 
xxxxxxxxxxxxxxxx 
xx 
xx 
xxxxxxxxx 
DD/MM/YY 
DD/MM/YY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) Modality Codes: 01 = Surgery, 02 = Radiation, 03 = Chemotherapy, 04 = Immunotherapy, 05 = Hormonal therapy,  
06 = Targeted Therapy  (sorafenib), 07 = Chemoembolization, 08 = Anti-viral therapy, 09 = Other 
(2) Intent Codes: 01 = Curative / Palliative, 02 = Adjuvant, 03 = Neo adjuvant, 04 = Diagnostic, 05 = Therapy of Viral Hepatitis,  
06 = Therapy for Complication of Portal Hypertension, 09 = Other (specify) 
(3) Best Response Codes: 01 = CR – Complete Response; 02 = PR – Partial Response; 03 = PD – Progressive Disease; 04 = SD – Stable Disease;  
09 = Unknown 
 
 
Programming Note: There may be multiple lines per subject.  
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 74 of 109   
 
 
 
 
 
 
 
Listing 16.2.3.5 
Cirrhosis / Virus Complications and Treatment 
 
 
Site/ Subject 
 
 
Treatment 
Modality 
Code (1) 
Modality Details 
Intent (2) 
 
 
Start Date 
 
 
Stop Date 
xxx/xxxx 
xxxxx 
xx 
xxxxxxxxxxxxxxxx 
xxxxxx 
DD/MM/YY 
DD/MM/YY 
xxx/xxxx 
xxxxx 
xx 
xxxxxxxxxxxxxxxx 
xxxxxx 
DD/MM/YY 
DD/MM/YY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) Modality Codes: 01 = Surgery, 02 = Radiation, 03 = Chemotherapy, 04 = Immunotherapy, 05 = Hormonal therapy, 
06 = Targeted Therapy (sorafenib),  07 = Chemoembolization, 08 = Anti-viral therapy, 09 = Other 
(2) Intent Codes: 01 = Curative / Palliative, 02 = Adjuvant, 03 = Neo adjuvant, 04 = Diagnostic, 05 = Therapy of Viral 
Hepatitis, 06 = Therapy for Complication of Portal Hypertension, 09 = Other (specify) 
 
 
Programming Note: There may be multiple lines per subject.  
 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 75 of 109   
 
 
 
 
 
 
 
Listing 16.2.3.6 
Medical History (Excluding Past HCC, Cirrhosis, and Viral Hepatitis-Related History) 
 
 
Site/ Subject 
 
 
Treatment 
Past findings or 
surgery? (1) 
Body System 
 
Finding or Procedure 
 
 
Start Date 
 
 
Stop Date 
xxx/xxxx 
xxxxx 
Yes 
xxxxxxxxx 
xxxxxxxxxxxx 
DD/MM/YY 
DD/MM/YY 
 
 
 
xxxxxxxxx 
xxxxxxxxxxxx 
DD/MM/YY 
DD/MM/YY 
xxx/xxxx 
xxxxx 
Yes 
xxxxxxxxx 
xxxxxxxxxxxx 
DD/MM/YY 
DD/MM/YY 
xxx/xxxx 
xxxxx 
No 
 
 
 
 
xxx/xxxx 
xxxxx 
Yes 
xxxxxxxxx 
xxxxxxxxxxxx 
DD/MM/YY 
DD/MM/YY 
 
 
 
 
 
 
 
 
 (1) Has the patient had any past medical findings or surgical procedures? 
 
 
Programming Note: There may be multiple lines per subject.  
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 76 of 109   
 
 
 
 
 
 
 
Listing 16.2.4.1 
Study Drug Accountability and Treatment Compliance 
 
 
Site/ Subject 
 
 
Treatment 
 
Total Number of 
Capsules 
Dispensed 
Total Number of 
Capsules 
Returned 
Date of  
Final Dose (1) 
Date of 
Baseline 
Visit 
 
Treatment 
Duration 
(Days) 
 
Compliance (%) 
xxx/xxxxx 
xxxxx 
xxx 
xxx 
DD/MM/YY 
DD/MM/YY 
xxx 
xx.x 
xxx/xxxxx 
xxxxx 
xxx 
xxx 
DD/MM/YY 
DD/MM/YY 
xxx 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) Date of Last Recorded Visit for subjects who are ongoing. 
The numbers of capsules dispensed and returned by visit are in the next listing. 
 
Programming Notes: Treatment Duration= date of final dose minus date of Baseline + 1. 
Compliance (%) =100*(total number of capsules dispensed over study - total number of capsules returned over study)/ (2*treatment duration). 
Total number of capsules dispensed over study = 65*sum of the Number of Bottles Dispensed from next listing. 
Total number of capsules returned over study = 65*sum of the Number of Unopened Bottles Returned from above table  
+ sum of Number of capsules returned (open bottle) from next listing. 
 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 77 of 109   
 
 
 
 
 
 
 
 
Listing 16.2.4.2 
Study Drug Accountability by Visit  
 
 
Site/ Subject 
 
 
Treatment 
 
Visit 
Date 
 
Treatment 
Number 
 
Number of 
Bottles 
Dispensed 
 
 
Comments 
 
Number of 
unopened 
bottles returned  
Number of 
capsules returned 
(open bottle) 
 
 
Comments 
xxx/xxxxx 
xxxxx 
Cycle 1 
xx/xxx/xxxxx 
xxxx 
xxx 
xxxxxx 
 
 
 
 
 
Cycle 2 
xx/xxx/xxxxx 
xxxx 
xxx 
xxxxxx 
xxx 
xxx 
xxxxxxxx 
 
 
Cycle 3 
xx/xxx/xxxxx 
xxxx 
xxx 
xxxxxx 
xxx 
xxx 
xxxxxxxx 
xxx/xxxxx 
xxxxx 
Cycle 1 
xx/xxx/xxxxx 
xxxx 
xxx 
xxxxxx 
 
 
 
 
 
Cycle 2 
xx/xxx/xxxxx 
xxxx 
xxx 
xxxxxx 
xxx 
xxx 
xxxxxxxx 
 
 
Cycle 3 
xx/xxx/xxxxx 
xxxx 
xxx 
xxxxxx 
xxx 
xxx 
xxxxxxxx 
 
 
Cycle 4 
xx/xxx/xxxxx 
xxxx 
xxx 
xxxxxx 
xxx 
xxx 
xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Note: Continue for all cycles.   
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 78 of 109   
 
 
 
 
 
 
 
 
Listing 16.2.5.1 
Time to Event 
 
Site/ 
Subject 
Treatment 
Date of 
First Dose 
Progressive 
Disease? 
Death? 
Date of 
Death 
Date of First 
Progression 
Date of Last 
Contact 
OS 
(months) 
TTP 
(months) 
PFS 
(months) 
xxx/xxxxx 
xxxx 
DD/MM/YY 
Yes 
Yes 
DD/MM/YY 
DD/MM/YY 
DD/MM/YY 
xx.x 
xx.x 
xx.x 
xxx/xxxxx 
xxxx 
DD/MM/YY 
Yes 
No 
 
DD/MM/YY 
DD/MM/YY 
xx.x * 
xx.x 
xx.x 
xxx/xxxxx 
xxxx 
DD/MM/YY 
No 
No 
 
 
DD/MM/YY 
xx.x * 
xx.x * 
xx.x * 
xxx/xxxxx 
xxxx 
DD/MM/YY 
No 
Yes 
DD/MM/YY 
 
DD/MM/YY 
xx.x 
xx.x *  
xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OS= Overall Survival (Time to Death due to any cause); TTP=Time to Progression; PFS= Progression-Free Survival (Time to Progression or Death) 
* indicates censored value. 
 
Programming Notes: If an event did not occur, leave the date of the event blank.  
Date of Last Contact is the last date known to be alive in next listing.  
Add * for censored values, defined as follows. 
OS is time to death due to any cause and is censored at date of last contact if death is not reported. 
TTP is time to progression and is censored at date of last contact (including death) if progression is not reported. 
PFS is time to progression or death and is censored at date of last contact if neither progression nor death is reported. 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 79 of 109   
 
 
 
 
 
 
 
Listing 16.2.5.2 
Survival Follow-up Contact Dates 
 
Site/ Subject 
Treatment 
Follow-up 
Date 
Is the Subject 
Alive? 
Last date known 
to be alive 
If not alive, date 
of death 
xxx/xxxxx 
xxxx 
DD/MM/YY 
xx 
DD/MM/YY 
DD/MM/YY 
 
 
DD/MM/YY 
xx 
DD/MM/YY 
DD/MM/YY 
 
 
DD/MM/YY 
xx 
DD/MM/YY 
DD/MM/YY 
xxx/xxxxx 
xxxx 
DD/MM/YY 
xx 
DD/MM/YY 
DD/MM/YY 
 
 
DD/MM/YY 
xx 
DD/MM/YY 
DD/MM/YY 
 
 
DD/MM/YY 
xx 
DD/MM/YY 
DD/MM/YY 
 
 
 
 
 
 
Includes all subjects who discontinue from dosing. 
 
Programming Notes: Continue for all follow-up dates.  
The CRF Page is to be completed for all subjects who discontinue from dosing. 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 80 of 109   
 
 
 
 
 
 
 
Listing 16.2.6.1.1 
Tumor Evaluations: Target Lesions 
 
Site/ 
Subject 
Treatment 
Cycle 
Lesion# 
Site 
Code (1) 
Description 
Assessment 
Date 
Method 
Code (2) 
Longest  
Diameter (LD) 
xxx/xxxx 
xxxxx 
Screening 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
Cycle 3 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
Cycle 5 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
(1) Site Codes: 
01 = Abdominal Wall, 02 = Adrenal, 03 = Bladder, 04 = Bone, 05 = Breast, 06 = CNS,  07 = Colon, 08 = Liver, 09 = Lung,  
10 = Lymph Nodes, 11 = Pancreas, 12 = Pelvis, 13 = Pleura, 14 = Rectum, 15 = Retroperitoneal Cavity, 16 = Retroperitoneum, 17 
= Small Intestine, 18 = Uterus, 99 = Other, specify 
 
(2) Method Codes: 
B = Bone Scan, C = Conventional CT scan, D = Direct Measure by Physical Exam, E = Endoscopy, L = Laparoscopy,  
M = Magnetic Resonance Imaging, S = Spiral CT scan, U = Ultrasound, X = X-Ray, O = Other, specify  
 
 
Programming Notes: Continue for all odd-numbered cycles.   
Sort listing by lesion within cycle. There is one line for each target lesion. 
 
Column “None?” has been deleted 
It was intended only for cases with assessments made and there were no target lesions detected.  
This would require “CR” for Target Lesions with disappearance of all Target Lesions; there were no such cases. 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 81 of 109   
 
 
 
 
 
 
 
Listing 16.2.6.1.2 
Summary of Target Lesions 
 
Site/ Subject 
Treatment 
Cycle 
Sum of Longest 
Diameters (mm) 
Smallest Sum 
On Study (mm) 
Percent 
Change from 
Smallest: 
Screening 
Sum on study 
Percent Change 
From Screening 
xxx/xxxx 
xxxxx 
Screening 
xx 
xx 
xxx 
xxx 
xxx 
 
 
Cycle 3 
xx 
xx 
xxx 
xxx 
xxx 
 
 
Cycle 5 
xx 
xx 
xxx 
xxx 
xxx 
xxx/xxxx 
xxxxx 
Screening 
xx 
xx 
xxx 
xxx 
xxx 
 
 
Cycle 3 
xx 
xx 
xxx 
xxx 
xxx 
 
 
Cycle 5 
xx 
xx 
xxx 
xxx 
xxx 
xxx/xxxx 
xxxxx 
Screening 
xx 
xx 
xxx 
xxx 
xxx 
 
 
Cycle 3 
xx 
xx 
xxx 
xxx 
xxx 
 
 
Cycle 5 
xx 
xx 
xxx 
xxx 
xxx 
 
 
Cycle 7 
xx 
xx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 “Smallest sum on study” at any visit refers to sums prior to, and including, the visit of interest, including the baseline sum of diameters. 
 
Programming Notes: Continue for all odd-numbered cycles. There is one line for each cycle.  
Column “None?” has been deleted 
It was intended only for cases with assessments made and there were no target lesions detected.  
This would require “CR” for Target Lesions with disappearance of all Target Lesions; there were no such cases. 
 
 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 82 of 109   
 
 
 
 
 
 
 
 
 
Listing 16.2.6.2 
Tumor Evaluations: Non-Target Lesions 
 
Site/ Subject 
Treatment 
Cycle 
None? 
Lesion# 
Site 
Code (1) 
Description 
Assessment 
Date 
Method 
Code (2) 
Status 
xxx/xxxx 
xxxxx 
Screening 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
Cycle 3 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
Cycle 5 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
Cycle 7 
None 
 
 
 
DD/MM/YY 
 
 
 
 
Cycle 9 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
xx 
xx 
xxxxxx 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
‘None?’ = ‘None’ if no non-target lesions were recorded 
(1) Site Codes: 
01 = Abdominal Wall, 02 = Adrenal, 03 = Bladder, 04 = Bone, 05 = Breast, 06 = CNS,  07 = Colon, 08 = Liver, 09 = Lung, 10 = Lymph Nodes, 
11 = Pancreas, 12 = Pelvis, 13 = Pleura, 14 = Rectum, 15 = Retroperitoneal Cavity, 16 = Retroperitoneum, 17 = Small Intestine, 18 = Uterus, 99 = 
Other, specify 
 
(2) Method Codes: 
B = Bone Scan, C = Conventional CT scan, D = Direct Measure by Physical Exam, E = Endoscopy, L = Laparoscopy, M = Magnetic Resonance 
Imaging, S = Spiral CT scan, U = Ultrasound, X = X-Ray, O = Other, specify  
 
 
Programming Notes: Continue for all odd-numbered cycles.   
Sort by lesion within cycle. There is one line for each non-target lesion. 
 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 83 of 109   
 
 
 
 
 
 
 
Listing 16.2.6.3.1 
Tumor Response  
 
Site/ Subject 
Treatment 
Cycle 
Assessment 
Date 
Response: 
Target 
Lesions (1) 
Response: 
Non-Target 
Lesions (2) 
Comment 
Overall 
Response (3) 
OR (4) 
DC (5) 
Best 
Response (6) 
xxx/xxxxx 
xxxx 
Cycle 3  
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxx/xxxxx 
xxxx 
Cycle 3 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
Cycle 5 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
530/006 
xxxx 
Cycle 3 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
Cycle 5 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
Cycle 7 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 9 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
Cycle 11 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
Cycle 13 (7) 
DD/MM/YY 
PR 
xxx 
 
PR 
xxx 
xxx 
 
 
 
Cycle 15 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
Cycle 29 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) CR= Complete Response, PR= Partial Response,  SD= Stable Disease,  PD= Progressive Disease 
(2) CR= Complete Response, PD= Progressive Disease, Non-CR/non-PD= Neither CR nor PD, NE= Not evaluated/ Unable to evaluate  
(3) CR= Complete Response, PR= Partial Response,  SD= Stable Disease, PD= Progressive Disease, Non-CR/non-PD= Neither CR nor PD, NE= Not evaluated/ Unable to evaluate 
(4) OR= Objective Response= Overall Response of CR or PR (Yes or No) 
(5) DC= Disease Control = Overall Response of CR,  PR, or SD (Yes or No) 
(6) Best Response = Best overall response recorded from the start of the study treatment until the end of study, in the order of CR, PR, SD, or PD from best to worst 
(7) Subject 530/006 ay Cycle 13 had Response: Target Lesions that met RECIST criteria for both PR and PD, included above as PR. 
 
 
Programming Notes: Continue for all odd-numbered cycles. 
Use “Comment” for “Response: Non-Target Lesions” = “Unable to evaluate (NE)”.  
Record “Best Response” only at visit(s) at which it occurs. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 84 of 109   
 
 
 
 
 
 
 
 
Listing 16.2.6.3.2 
Tumor Response (Investigator Assessments) 
 
Site/ Subject 
Treatment 
Cycle 
Assessment 
Date 
Response: 
Target 
Lesions (1) 
Response: 
Non-Target 
Lesions (2) 
Comment 
Overall 
Response (3) 
OR (4) 
DC (5) 
Best 
Response (6) 
xxx/xxxxx 
xxxx 
Cycle 3  
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxx/xxxxx 
xxxx 
Cycle 3 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
Cycle 5 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
530/006 
xxxx 
Cycle 3 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
Cycle 5 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
Cycle 7 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 9 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
Cycle 11 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
Cycle 13 (7) 
DD/MM/YY 
PR 
xxx 
 
PD 
xxx 
xxx 
 
 
 
Cycle 15 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
Cycle 29 
DD/MM/YY 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) CR= Complete Response, PR= Partial Response,  SD= Stable Disease,  PD= Progressive Disease 
(2) CR= Complete Response, PD= Progressive Disease, Non-CR/non-PD= Neither CR nor PD, NE= Not evaluated/ Unable to evaluate  
(3) CR= Complete Response, PR= Partial Response,  SD= Stable Disease, PD= Progressive Disease, Non-CR/non-PD= Neither CR nor PD, NE= Not evaluated/ Unable to evaluate 
(4) OR= Objective Response= Overall Response of CR or PR (Yes or No) 
(5) DC= Disease Control = Overall Response of CR,  PR, or SD (Yes or No) 
(6) Best Response = Best overall response recorded from the start of the study treatment until the end of study, in the order of CR, PR, SD, or PD from best to worst 
(7) Subject 530/006 ay Cycle 13 had Response: Target Lesions that met RECIST criteria for both PR and PD, included above as PD. 
 
 
Programming Notes: Continue for all odd-numbered cycles. 
Use “Comment” for “Response: Non-Target Lesions” = “Unable to evaluate (NE)”.  
Record “Best Response” only at visit(s) at which it occurs. 
Include Tumor Responses as recorded on CRF, including EOS Visit, the Follow-up Visit, and Unscheduled Visits. 
 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 85 of 109   
 
 
 
 
 
 
 
Listing 16.2.6.4 
Biomarkers: AFP and WBC A3AR 
 
Site/ Subject 
Treatment 
Cycle 
Date 
alpha-fetoproterin 
(AFP) (1) 
CFB in 
AFP 
WBC A3AR  
Expression Level  
CFB in WBC A3AR  
Expression Level 
xxx/xxxxx 
xxxx 
Baseline 
DD/MM/YY 
xxx 
 
xxx 
 
 
 
Cycle 2 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
Cycle 3 
DD/MM/YY 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 4 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
Cycle 5 
DD/MM/YY 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
xxx/xxxxx 
xxxx 
Baseline 
DD/MM/YY 
xxx 
 
xxx 
 
 
 
Cycle 2 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
Cycle 3 
DD/MM/YY 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 4 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
Cycle 5 
DD/MM/YY 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFB=Change from Baseline  
(1) H=Abnormal High, L=Abnormal Low  
Normal ranges are given at the end of the listing. 
Baseline=Cycle 1 Day 1 
 
Programming Note: Continue for all cycles.  
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 86 of 109   
 
 
 
 
 
 
 
 
Listing 16.2.6.4 
 
Biomarkers: AFP and WBC A3AR   
Normal Ranges 
 
Parameter 
Low 
High 
AFP 
 
xx 
Normal range for WBC A3AR not specified 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 87 of 109   
 
 
 
 
 
 
 
Listing 16.2.6.5.1 
Hepatitis B Viral Load  
 
Site/ Subject 
Treatment 
Visit 
Date 
Screening 
Serology 
Sample  
Taken? (1) 
Viral Load 
(IU/mL) 
Log (Viral Load)  
CFB in  
Log (Viral Load)  
xxx/xxxxx 
xxxx 
Baseline 
DD/MM/YY 
xxxxxxxx 
xxx 
xxxxxx 
xxxx.xx 
 
 
 
Cycle 3 
DD/MM/YY 
 
xxx 
xxxxxx 
xxxx.xx 
xxxx.xx 
 
 
Cycle 5 
DD/MM/YY 
 
xxx 
xxxxxx 
xxxx.xx 
xxxx.xx 
 
 
Cycle 7 
DD/MM/YY 
 
xxx 
xxxxxx 
xxxx.xx 
xxxx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) Yes, No, or NA 
Should include only subjects with positive serology at Screening, per protocol. Others are included if viral load was recorded (Listing 16.2.3.3). 
CFB=Change from Baseline  
Baseline=Cycle 1 Day 1 
Log (Value) is the base 10 logarithm of the value.  
 
 
Programming Notes: Continue for all odd-numbered cycles. Include Screening Serology as “Positive” or “Negative”. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 88 of 109   
 
 
 
 
 
 
 
 
Listing 16.2.6.5.2 
Hepatitis C Viral Load  
 
Site/ Subject 
Treatment 
Visit 
Date 
Screening 
Serology 
Sample  
Taken? (1) 
Viral Load 
(IU/mL) 
Log (Viral Load)  
CFB in  
Log (Viral Load)  
xxx/xxxxx 
xxxx 
Baseline 
DD/MM/YY 
xxxxxxxx 
xxx 
xxxxxx 
xxxx.xx 
 
 
 
Cycle 3 
DD/MM/YY 
 
xxx 
xxxxxx 
xxxx.xx 
xxxx.xx 
 
 
Cycle 5 
DD/MM/YY 
 
xxx 
xxxxxx 
xxxx.xx 
xxxx.xx 
 
 
Cycle 7 
DD/MM/YY 
 
xxx 
xxxxxx 
xxxx.xx 
xxxx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) Yes, No, or NA 
Should include only subjects with positive serology at Screening, per protocol. Others are included if viral load was recorded (Listing 16.2.3.3). 
CFB=Change from Baseline  
Baseline=Cycle 1 Day 1 
Log (Value) is the base 10 logarithm of the value.  
 
 
Programming Notes: Continue for all odd-numbered cycles. Include Screening Serology as “Positive” or “Negative”. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 89 of 109   
 
 
 
 
 
 
 
Listing 16.2.7 
Adverse Events 
 
Site/ 
Subject 
Treatment 
System Organ Class / 
Preferred Term/ 
Verbatim Term 
Start Date 
Stop Date (1) 
Duration (2) 
Severity 
Grade (3) 
Frequency (4) Relation (5) 
Action 
Taken (6) Outcome (7) Serious? 
xxx/xxxx 
xxxxx 
xxxxxx / 
  xxxxxx/  
    xxxxxxx 
DD/MM/YY 
DD/MM/YY 
x 
x 
x 
x 
x 
x 
xx 
xxx/xxxx 
xxxxx 
xxxxxx / 
  xxxxxx/  
    xxxxxxx 
DD/MM/YY 
DD/MM/YY 
x 
x 
x 
x 
x 
x 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) O=AE ongoing 
(2) Duration (days)= Stop Date – Start Date + 1; Duration =Date of Last Dose – Start Date + 1 if AE is ongoing 
(3) Severity Grade: 1=Mild, 2=Moderate, 3=Severe or medically significant but not immediately life-threatening, 4=Life-threatening consequences, or 5=Death related to AE.  
(4) Frequency: 1= Single episode 2= Intermittent 3= Continuous 
(5) Relationship: 1= Definitely related 2= Probably related 3= Possibly related 4= Not related 
(6) Action Taken: 0= None 1= Medication TX 2= Non-medication TX 3= Hospitalization 4= Study drug delayed, 5= Study drug discontinued 
(7) Outcome: 1= Resolved 2= Resolved with sequelae 3= Unresolved 4= Death 
Sorted by Start Date, then alphabetically by SOC and Preferred Term within subject. 
 
Programming Note: Sort by Start Date, then alphabetically by SOC and Preferred Term within subject for AEs starting on the same date. 
 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 90 of 109   
 
 
 
 
 
 
 
 
Listing 16.2.8.1 
Clinical Laboratory Evaluations: Hematology 
 
Site/ Subject 
Treatment 
Visit 
Day 
Date 
Laboratory Parameter (Units) 
Value (1) 
CFB  
xxx/xxxx 
xxxxx 
Pre-Study 
 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
Baseline  
 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
Cycle 1 
8 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
Cycle 1 
15 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
Cycle 2 
1 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
Cycle 2 
15 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
Cycle 3 
1 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
(1) H=Abnormal High, L=Abnormal Low  
Normal ranges are given at the end of the listing. 
CFB=Change from Baseline  
Baseline=Cycle 1 Day 1 (or Pre-Study if <= 3 days prior to Cycle 1 Day 1 or if value at Cycle 1 Day 1 is missing) 
 
 
Programming Note: Continue for all cycles, Days 1 and 15. 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 91 of 109   
 
 
 
 
 
 
 
 
Listing 16.2.8.1 
 
 Clinical Laboratory Evaluations: Hematology 
Normal Ranges 
 
Parameter 
Gender 
Age (Years) 
Low  - High 
BASOPHILS (%) 
– 
18 - 65+ 
0 - 2 
BASOPHILS ABSOLUTE (GI/L) 
– 
18 - 65+ 
0 - 0.2 
EOSINOPHILS (%) 
– 
18 - 65+ 
0 - 7 
EOSINOPHILS ABSOLUTE (GI/L) 
– 
18 - 65+ 
0.05 - 0.55 
HEMATOCRIT  (1)  
Male  
18 - 64 
0.41 - 0.50 
 
Male 
65+ 
0.36 - 0.49 
 
Female 
18 - 64 
0.35 - 0.46 
 
Female  
65+ 
0.33 - 0.46 
HEMOGLOBIN  (G/L) 
Male  
18 - 64 
138 - 172 
 
Male 
65+ 
118 - 168 
 
Female 
18 - 64 
120 – 156 
 
Female  
65+ 
111 - 155 
LYMPHOCYTES (%) 
– 
18 - 65+ 
16 - 46 
LYMPHOCYTES ABSOLUTE (GI/L) 
– 
18 - 65+ 
0.85 - 4.10 
MONOCYTES (%) 
– 
18 - 65+ 
0 - 12 
MONOCYTES ABSOLUTE (GI/L) 
– 
18 - 65+ 
0.2 - 1.1 
PLATELET COUNT (GI/L) 
– 
18 - 65+ 
130 - 400 
RED CELL COUNT (TI/L) 
Male 
18 - 64  
4.4 - 5.8 
 
Male 
65+  
3.7 - 5.5 
 
Female 
18 - 64  
3.9 - 5.2 
 
Female 
65+  
3.6 - 5.1 
RETICULOCYTES (%) 
– 
18 - 65+ 
0.5 - 2.3 
RETICULOCYTES, ABS (10e9/L) 
– 
18 - 65+ 
25 - 85 
TOTAL NEUTROPHILS (%) 
– 
18 - 65+ 
40 - 75 
TOTAL NEUTROPHILS AB (GI/L) 
– 
18 - 65+ 
1.8 – 8.0 
WHITE CELL COUNT (GI/L) 
– 
18 - 65+ 
3.8 - 10.8 
 
 
 
 
Ranges are given for adults (age at least 18 years). 
Age (Years) = “18 - 65+” indicates that there is no restriction on normal due to age in adults. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 92 of 109   
 
 
 
 
 
 
Listing 16.2.8.2 
Clinical Laboratory Evaluations: Blood Chemistry 
 
Site/ Subject 
Treatment 
Visit 
Day 
Date 
Laboratory Parameter (Units) 
Value (1) 
CFB  
xxx/xxxx 
xxxxx 
Pre-Study 
 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
Baseline  
 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
Cycle 1 
8 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
Cycle 1 
15 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
Cycle 2 
1 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
Cycle 2 
15 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
Cycle 3 
1 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
xxx 
 
(1) H=Abnormal High, L=Abnormal Low  
Normal ranges are given at the end of the listing. 
CFB=Change from Baseline  
Baseline=Cycle 1 Day 1 (or Pre-Study if <= 3 days prior to Cycle 1 Day 1 or if value at Cycle 1 Day 1 is missing) 
 
 
Programming Note: Continue for all cycles, Days 1 and 15.  
 
] 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 93 of 109   
 
 
 
 
 
 
 
Listing 16.2.8.2 
 
 Clinical Laboratory Evaluations: Blood Chemistry  
Normal Ranges 
 
Parameter 
Gender 
Age (Years) 
Low  - High 
ALAT (SGPT) (U/L) 
– 
18 - 65+ 
0 - 48 
ALBUMIN (G/L) 
– 
18 - 65+ 
32 - 50 
ALKALINE PHOSPHATASE (U/L) 
– 
20+  
20 - 125 
ASAT (SGOT) (U/L) 
– 
18 - 64 
0 - 42 
 
– 
65+ 
0 - 55 
BILIRUBIN, DIRECT (UMOL/L) 
– 
18 - 65+ 
0 - 6 
BILIRUBIN, TOTAL (UMOL/L) 
– 
18 - 65+ 
0 - 22 
CALCIUM (MMOL/L) 
– 
18 - 65+ 
2.12 - 2.56 
CARBON DIOXIDE (CO2) (MMOL/L) 
– 
18 - 65+ 
20 - 32 
CHLORIDE (MMOL/L) 
– 
18 - 65+ 
95 - 108 
GLUCOSE (MMOL/L) 
– 
18 - 49  
3.9 - 6.4 
 
– 
50+  
3.9 - 6.9 
LACTIC DEHYDROGENASE (U/L) 
– 
18 - 64 
0 - 250 
 
– 
65+ 
0 - 270 
PHOSPHORUS INORGANIC (MMOL/L) 
– 
18 - 64 
0.80 - 1.45 
 
– 
65+ 
0.7 - 1.4 
POTASSIUM (MMOL/L) 
– 
18 - 65+ 
3.5 - 5.3 
PROTEIN, TOTAL SERUM (G/L) 
– 
18 - 64 
60 - 85 
 
– 
65+ 
58 - 81 
SODIUM (MMOL/L) 
– 
18 - 65+ 
135 - 146 
UREA NITROGEN (MMOL/L) 
– 
18 - 64 
2.5 - 9 
 
– 
65+ 
2.5 - 10.5 
URIC ACID (UMOL/L) 
Male 
18 - 65+ 
240 - 510 
 
Female 
18 - 65+ 
150 - 450 
 
 
 
 
Ranges are given for adults (age at least 18 years). 
Age (Years) = “18 - 65+” indicates that there is no restriction on normal due to age in adults. 
 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 94 of 109   
 
 
 
 
 
 
Listing 16.2.8.2 
 
 Clinical Laboratory Evaluations: Blood Chemistry  
Normal Ranges (CREATININE ENZ) 
 
Parameter 
Gender 
Age (Years) 
Low  - High 
CREATININE ENZ, SER (UMOL/L) 
Male 
20 - 29  
70.7 - 114.9 
 
Male 
30 - 39  
69.8 - 117.6 
 
Male 
40 - 49  
69.0 - 118.5 
 
Male 
50 - 59  
67.2 - 129.1 
 
Male 
60 - 69  
67.2 - 129.1 
 
Male 
70+  
59.2 - 136.1 
 
Female 
30 - 39  
51.3 - 93.7 
 
Female 
40 - 49  
52.2 - 94.6 
 
Female 
50 - 59  
53.0 - 97.2 
 
Female 
60 - 69  
53.0 - 104.3 
 
Female 
70+  
55.7 - 107.8 
 
 
 
 
Ranges are given for adults (age at least 18 years). 
Age (Years) = “18 - 65+” indicates that there is no restriction on normal due to age in adults. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 95 of 109   
 
 
 
 
 
 
 
Listing 16.2.8.3 
Clinical Laboratory Evaluations: Coagulation 
 
 
 
 
 
 
PTT 
 
INR 
 
PT 
 
Site/ 
Subject 
Treatment 
Visit 
Day 
Date 
Value (1) 
CFB  
Value (1) 
CFB  
Value (1) 
CFB  
xxx/xxxx 
xxxxx 
Pre-Study 
 
MM/DD/YYYY 
xxx 
 
xxx 
 
xxx 
 
 
 
Baseline  
 
MM/DD/YYYY 
xxx 
 
xxx 
 
xxx 
 
 
 
Cycle 1 
8 
MM/DD/YYYY 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
15 
MM/DD/YYYY 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 2 
1 
MM/DD/YYYY 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
15 
MM/DD/YYYY 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 3 
1 
MM/DD/YYYY 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
15 
MM/DD/YYYY 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
PTT= Partial Thromboplastin Time; INR= International Normalized Ratio; PT= Prothrombin Time 
(1) H=Abnormal High, L=Abnormal Low  
Normal ranges are given at the end of the listing. 
CFB=Change from Baseline  
Baseline=Cycle 1 Day 1 (or Pre-Study if <= 3 days prior to Cycle 1 Day 1 or if value at Cycle 1 Day 1 is missing) 
 
 
Programming Note: Continue for all cycles, Days 1 and 15. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 96 of 109   
 
 
 
 
 
 
 
 
 
Listing 16.2.8.3  
 
Clinical Laboratory Evaluations: Coagulation 
Normal Ranges 
 
Parameter 
Gender 
Age (Years) 
Low  - High 
PTT 
– 
18 - 65+ 
22 - 34 
INR 
– 
18 - 65+ 
0.9 - 1.1 
PT 
– 
18 - 65+ 
9 - 11.5 
 
 
 
 
Ranges are given for adults (age at least 18 years). 
Age (Years) = “18 - 65+” indicates that there is no restriction on normal due to age in adults. 
 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 97 of 109   
 
 
 
 
 
 
 
 
Listing 16.2.8.4 
Clinical Laboratory Evaluations: Urinalysis 
 
Site/ Subject 
Treatment 
Visit 
Day 
Date 
Laboratory Parameter (Units) 
Value 
xxx/xxxx 
xxxxx 
Pre-Study 
 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
Baseline  
 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
Cycle 1 
8 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
Cycle 1 
15 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
Cycle 2 
1 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
Cycle 2 
15 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
Cycle 3 
1 
MM/DD/YYYY 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
 
 
 
 
XXXXXXXXXXXXXXXXXXXXX (XXX) 
xxx 
 
Baseline=Cycle 1 Day 1 (or Pre-Study if <= 3 days prior to Cycle 1 Day 1 or if value at Cycle 1 Day 1 is missing) 
 
 
Programming Notes: Continue for all cycles, Days 1 and 15. CFB is not computed for any urinalysis parameter. 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 98 of 109   
 
 
 
 
 
 
 
Listing 16.2.8.5 
Clinical Laboratory Evaluations: Thyroid Function 
 
 
 
 
 
T3 (Unit) 
T4 (Unit) 
TSH (Unit) 
Site/ Subject 
Treatment 
Visit 
Date 
Value (1) 
CFB  
Value (1) 
CFB  
Value (1) 
CFB  
xxx/xxxx 
xxxxx 
Pre-Study 
MM/DD/YYYY 
xxx 
 
xxx 
 
xxx 
 
 
 
Cycle 1 
MM/DD/YYYY 
xxx 
 
xxx 
 
xxx 
 
 
 
Cycle 2 
MM/DD/YYYY 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 3 
MM/DD/YYYY 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxx/xxxx 
xxxxx 
Pre-Study 
MM/DD/YYYY 
xxx 
 
xxx 
 
xxx 
 
 
 
Cycle 1 
MM/DD/YYYY 
xxx 
 
xxx 
 
xxx 
 
 
 
Cycle 2 
MM/DD/YYYY 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 3 
MM/DD/YYYY 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
(1) H=Abnormal High, L =Abnormal Low  
Normal ranges are given at the end of the listing. 
CFB=Change from Baseline 
Baseline=Cycle 1 (or Pre-Study if <= 3 days prior to Cycle 1 Day 1 or if value at Cycle 1 Day 1 is missing) 
 
 
Programming Notes: Continue for all cycles. Include units. 
Column for “Day” deleted since Thyroid Function assessed only at Day 1.   
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 99 of 109   
 
 
 
 
 
 
 
 
 
Listing 16.2.8.5  
 
Clinical Laboratory Evaluations: Thyroid Function  
Normal Ranges 
 
Parameter 
Gender 
Age (Years) 
Low  - High 
T3 
– 
18 - 65+ 
3.5 - 6.5 
T4 
– 
18 - 65+ 
10.3 - 23.2 
TSH 
– 
20+  
0.4 - 4.5 
 
 
 
 
Ranges are given for adults (age at least 18 years). 
Age (Years) = “18 - 65+” indicates that there is no restriction on normal due to age in adults. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 100 of 109   
 
 
 
 
 
 
Listing 16.2.8.6 
 Pregnancy Test 
 
 
Site/ Subject 
Treatment 
 
Visit 
Test Date 
 
Result Not Done? Not Applicable? 
Menopausal date/ 
Other Specify 
xxx/xxxxx 
xxxxx 
Pre-Study 
DD/MM/YY 
xxxx 
 
 
 
 
 
Cycle 1 
DD/MM/YY 
xxxx 
 
 
 
 
 
Cycle 2 
DD/MM/YY 
 
xxxx 
 
 
 
 
Cycle 3 
DD/MM/YY 
xxxx 
 
 
 
xxx/xxxxx 
xxxxx 
Pre-Study 
DD/MM/YY 
 
 
xxxx 
 
 
 
Cycle 1 
DD/MM/YY 
 
 
xxxx 
 
 
 
Cycle 2 
DD/MM/YY 
 
 
xxxx 
 
 
 
Cycle 3 
DD/MM/YY 
 
 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Note: Continue for all cycles. For “Not Applicable?”, enter reason if not applicable. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 101 of 109   
 
 
 
 
 
 
 
Listing 16.2.9.1 
Vital Signs  
 
Site/ Subject 
Treatment 
Visit 
Time 
Systolic BP 
(mmHg) 
Diastolic BP 
(mmHg) 
Temperature 
(degrees C) 
Respiratory Rate  
(/min) 
Pulse  
(beats/min) 
Value 
CFB 
Value 
CFB 
Value 
CFB 
Method 
Value 
CFB 
Value 
CFB 
xxx/xxxxx 
xxxx 
Pre-Study 
 
xxx 
 
xxx 
 
xxx 
 
x 
xxx 
 
xxx 
 
 
 
Cycle 1 
Day 1 
xxx 
 
xxx 
 
xxx 
 
x 
xxx 
 
xxx 
 
 
 
 
Day 1 
Hour 1  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
x 
xxx 
xxx 
xxx 
xxx 
 
 
 
Day 1 
Hour 2 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
x 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 8 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
x 
xxx 
xxx 
xxx 
xxx 
 
 
 
Day 15 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
x 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 2 
Day 1 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
x 
xxx 
xxx 
xxx 
xxx 
 
 
 
Day 15 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
x 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 3 
Day 1 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
x 
xxx 
xxx 
xxx 
xxx 
 
 
 
Day 15 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
x 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFB=Change from Baseline 
Baseline=Cycle 1 Day 1 (or Pre-Study if  value at Cycle 1 Day 1 is missing) 
Method= ‘O’ for oral, ‘A’ for Axillary 
 
Programming Note: Continue for all visits (Days 1 and 15 of each cycle, Day 8 of Cycle 1, and Hours 1, 2, 3, 4, 6 and 8 on Cycle 1 Day 1) 
with CFB.  
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 102 of 109   
 
 
 
 
 
 
 
 
Listing 16.2.9.2 
Weight, Height, and BMI  
 
Site/ Subject 
Treatment 
Visit 
 
Height (cm) 
Weight (kg) 
BMI (kg/m^2) 
Time 
Value 
CFB 
Value 
CFB 
xxx/xxxxx 
xxxx 
Pre-Study 
 
xxx 
xxx 
 
xxx 
 
 
 
Cycle 1 
Day 1 
 
xxx 
 
xxx 
 
 
 
 
Day 8 
 
xxx 
xxx 
xxx 
xxx 
 
 
 
Day 15 
 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 2 
Day 1 
 
xxx 
xxx 
xxx 
xxx 
 
 
 
Day 15 
 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 3 
Day 1 
 
xxx 
xxx 
xxx 
xxx 
 
 
 
Day 15 
 
xxx 
xxx 
xxx 
xxx 
xxx/xxxxx 
xxxx 
Pre-Study 
 
xxx 
xxx 
 
xxx 
 
 
 
Cycle 1 
Day 1 
 
xxx 
 
xxx 
 
 
 
 
Day 8 
 
xxx 
xxx 
xxx 
xxx 
 
 
 
Day 15 
 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 2 
Day 1 
 
xxx 
xxx 
xxx 
xxx 
 
 
 
Day 15 
 
xxx 
xxx 
xxx 
xxx 
 
 
Cycle 3 
Day 1 
 
xxx 
xxx 
xxx 
xxx 
 
 
 
Day 15 
 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
CFB=Change from Baseline 
Baseline=Cycle 1 Day 1 (or Pre-Study if <= 3 days prior to Cycle 1 Day 1 or if value at Cycle 1 Day 1 is missing) 
BMI=Body mass index. 
BMI is computed using Height recorded at Pre-Study. 
 
Programming Note: Continue for all cycles. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 103 of 109   
 
 
 
 
 
 
 
 
Listing 16.2.9.3 
ECOG Performance Status 
 
Site/ Subject 
Treatment 
Visit 
Assessment 
Date 
ECOG PS 
CFB  
ECOG PS 
xxx/xxxxx 
xxxx 
Pre-Study 
DD/MM/YY 
xxx 
 
 
 
Cycle 1 
DD/MM/YY 
xxx 
 
 
 
Cycle 2 
DD/MM/YY 
xxx 
xxx 
 
 
Cycle 3 
DD/MM/YY 
xxx 
xxx 
 
 
Cycle 4 
DD/MM/YY 
xxx 
xxx 
xxx/xxxxx 
xxxx 
Pre-Study 
DD/MM/YY 
xxx 
 
 
 
Cycle 1 
DD/MM/YY 
xxx 
 
 
 
Cycle 2 
DD/MM/YY 
xxx 
xxx 
 
 
Cycle 3 
DD/MM/YY 
xxx 
xxx 
 
 
Cycle 4 
DD/MM/YY 
xxx 
xxx 
 
 
 
 
 
 
CFB=Change from Baseline 
Baseline=Cycle 1 Day 1 (or Pre-Study if <= 3 days prior to Cycle 1 Day 1 or if value at Cycle 1 Day 1 is missing) 
PS = Performance Status 
0=Normal activity, 1=Symptoms but ambulatory, 2= In bed <50% of time, 3=In bed >50% of time, 4=100% bedridden 
 
 
 
Programming Notes: Continue for all cycles. Record CFB as Decrease, No Change, or Increase. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 104 of 109   
 
 
 
 
 
 
 
 
 
Listing 16.2.10.1 
Electrocardiogram (ECG) – Continuous Variables 
 
 
 
 
 
 
 
 
Interval (msec) 
Heart Rate 
(bpm) 
PR 
QRS 
QT 
QTcF (1) 
Site/ 
Subject 
Treatment 
Visit 
Day 
Hour 
Time 
Value 
CFB 
Value 
CFB 
Value 
CFB 
Value 
CFB 
Value 
CFB 
xxx/xxxxx 
xxxxxxx 
Pre-Study 
 
 
xx:xx 
xx 
 
xx 
 
xx 
 
xx 
 
xx 
 
 
 
Cycle 1 
1 
0 
xx:xx 
xx 
 
xx 
 
xx 
 
xx 
 
xx 
 
 
 
 
 
2 
xx:xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
4 
xx:xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
6 
xx:xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
8 
0 
xx:xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
2 
xx:xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
4 
xx:xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
6 
xx:xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
15 
0 
xx:xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Cycle 2 
1 
0 
xx:xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
15 
0 
xx:xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Cycle 3 
1 
0 
xx:xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
15 
0 
xx:xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hour 0=Pre-Dose 
CFB=Change from Baseline  
Baseline=Cycle 1 Day 1 Hour 0 (or Pre-Study if the value at Cycle 1 Day 1 is missing) 
(1) QTcF=QT Correction: Fridericia. 
 
 
Programming Notes: Continue for QRS Complex (msec), PR Interval (msec), and QTcF (msec) in that order and all visits (Pre-Study, Pre-
dose on Days 1 and 15 of all cycles, Pre-dose on Day 8 of Cycle 1, and at 2, 4, and 6 hours post-dose on Days 1 and 8 of Cycle 1) with CFB. 
Compute QTcF=QT*(HR/60)1/3. 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 105 of 109   
 
 
 
 
 
 
 
 
 
Listing 16.2.10.2 
Electrocardiogram (ECG) – Categorical Variables 
 
Site/ Subject 
Treatment 
Visit 
Day 
Hour 
Time 
Overall 
Impression (1) 
ST Segment 
Cardiac 
Rhythm 
xxx/xxxxx 
xxxx 
Pre-Study 
 
 
 
xx 
xx 
xx 
 
 
Cycle 1 
1 
0 
xx:xx 
xx 
xx 
xx 
 
 
 
 
2 
xx:xx 
xx 
xx 
xx 
 
 
 
 
4 
xx:xx 
xx 
xx 
xx 
 
 
 
 
6 
xx:xx 
xx 
xx 
xx 
 
 
 
8 
0 
xx:xx 
xx 
xx 
xx 
 
 
 
 
2 
xx:xx 
xx 
xx 
xx 
 
 
 
 
4 
xx:xx 
xx 
xx 
xx 
 
 
 
 
6 
xx:xx 
xx 
xx 
xx 
 
 
 
15 
0 
xx:xx 
xx 
xx 
xx 
 
 
Cycle 2 
1 
0 
xx:xx 
xx 
xx 
xx 
 
 
 
15 
0 
xx:xx 
xx 
xx 
xx 
 
 
Cycle 3 
1 
0 
xx:xx 
xx 
xx 
xx 
 
 
 
15 
0 
xx:xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(1) 1=Normal, 2=Abnormal Not Clinically Significant, 3= Abnormal Clinically Significant 
Hour 0 = Pre-Dose    
 
 
Programming Note: Continue for all visits (Pre-Study, Pre-dose on Days 1 and 15 of all cycles, Pre-dose on Day 8 of 
Cycle 1, and at 2, 4, and 6 hours post-dose on Days 1 and 8 of Cycle 1). 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 106 of 109   
 
 
 
 
 
 
 
 
Listing 16.2.11.1 
Physical Examination at Pre-Study Visit 
  
Site/ Subject 
Treatment 
Body System 
Result 
Description If ‘Abnormal’ 
xxx/xxxxx 
xxxxx 
General Appearance 
Normal 
 
 
 
Head and Neck 
Normal 
 
 
 
Eyes, Ears, Nose, Throat 
Abnormal 
xxxxx 
 
 
Skin 
Normal 
 
 
 
Chest / Lungs / Breast 
Normal 
 
 
 
Heart 
Normal 
 
 
 
Abdomen 
Abnormal 
xxxxx 
 
 
Genitourinary 
Normal 
 
 
 
Extremities 
Normal 
 
 
 
Musculoskeletal 
Normal 
 
 
 
Lymph Nodes 
Abnormal 
xxxxx 
 
 
Neurological 
Normal 
 
 
 
Other 
Normal 
xxxxx 
xxx/xxxxx 
xxxxx 
General Appearance 
Normal 
 
 
 
Head and Neck 
Normal 
 
 
 
Eyes, Ears, Nose, Throat 
Normal 
 
 
 
Skin 
Normal 
 
 
 
Chest / Lungs / Breast 
Normal 
 
 
 
Heart 
Not Done 
 
 
 
Abdomen 
Normal 
 
 
 
Genitourinary 
Normal 
 
 
 
Extremities 
Normal 
 
 
 
Musculoskeletal 
Normal 
 
 
 
Lymph Nodes 
Abnormal 
xxxxx 
 
 
Neurological 
Normal 
 
 
 
Other 
Not Done 
 
 
 
 
 
 
 
Programming Note: Record result as ‘Normal’, ‘Abnormal’, or ‘Not Done’ 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 107 of 109   
 
 
 
 
 
 
 
 
Listing 16.2.11.2 
Physical Examination 
  
Site/ Subject 
Treatment 
Visit 
Screening 
<= 3 days from 
Baseline? 
 
Clin, Sig, 
Changes (1) 
Body System 
Result 
Description 
If different From  
Previous Assessment 
xxx/xxxxx 
xxxxx 
Cycle 1 
Day 1 
No 
No 
 
 
 
 
 
Cycle 1 
Day 8 
 
No 
 
 
 
 
 
Cycle 1 
Day 15 
 
No 
 
 
 
 
 
Cycle 2 
Day 1 
 
Yes 
Eyes, Ears, Nose, Throat 
Abnormal 
xxxxx 
 
 
 
 
Yes 
xxxxxxxxxxxxxxx 
xxxxxxx 
xxxxxxxxxxxxxx 
 
 
Cycle 2 
Day 15 
 
No 
 
 
 
 
 
Cycle 3 
Day 1 
 
Yes 
Lymph Nodes 
xxxxxxx 
xxxxx 
 
 
Cycle 3 
Day 15 
 
No 
 
 
 
 
 
Cycle 4 
Day 1 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxx/xxxxx 
xxxxx 
Cycle 1 
Day 1 
Yes 
 
 
 
 
 
 
Cycle 1 
Day 8 
 
No 
 
 
 
 
 
Cycle 1 
Day 15 
 
No 
 
 
 
 
 
Cycle 2 
Day 1 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
(1) Are there any clinically significant changes from the physical examination conducted at the previous assessment? 
Baseline=Cycle 1 Day 1 
 
Programming Notes: Continue for other cycles. If there are ‘No’ clinically significant changes from the physical examination conducted at 
the previous assessment, then the assessments for individual body systems should not be completed.  
If “Clin, Sig, Changes” = ‘Yes’, then results should be recorded for at least one body systems with a “Result” differing from the previous 
assessment list. If “Screening <= 3 days from Baseline?” is Yes, there should be no responses for Cycle 1 Day 1. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 108 of 109   
 
 
 
 
 
 
 
Listing 16.2.12 
Prior and Concomitant Medications 
 
Site/ Subject 
Treatment 
Medication 
ATC Level 3 
Reason for Use 
AE no. 
(1) 
Dose & Units 
Regimen 
Route (2) 
Start Date  
Stop Date 
(3) 
xxx/xxxxx 
xxxxx 
xxxx 
xxxx 
xxxxx 
x 
xxxx 
xxxx 
xx 
DD/MM/YY 
DD/MM/YY 
xxx/xxxxx 
xxxxx 
xxxx 
xxxx 
xxxxx 
x 
xxxx 
xxxx 
xx 
DD/MM/YY 
DD/MM/YY 
xxx/xxxxx 
xxxxx 
xxxx 
xxxx 
xxxxx 
x 
xxxx 
xxxx 
xx 
DD/MM/YY 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes medications taken within 30 days prior to Screening Visit. 
(1) Blank if Not Applicable 
(2) 1=PO; 2=IV; 3=SC; 5=IM; 11=T; 12=OU,OS,OD; 13=AU,AS,AD; 14=IN; 15=PV; 16=PR; 24=SL; 30=BUC; 37=IA; 71=NG; 136=INH; 358=TD; 135=Other; 139= Unknown 
(3) O=Ongoing 
 
 
 
Programming Note: Sort by start date for each subject. 
 
 
 


CF102-201HCC 
Statistical Analysis Plan Tables and Listings 
Page 109 of 109   
 
 
 
 
 
 
 
 
Listing 16.2.13 
Investigator Comments 
 
Site/ Subject 
Treatment 
Date Event Occurred 
or Study Visit 
CRF Page(s) 
Description of Event/Comment 
xxx/xxxxx 
xxxxx 
DD/MM/YY 
xx 
xxxxxxxxxxxx 
xxx/xxxxx 
xxxxx 
DD/MM/YY 
xx 
xxxxxxxxxxxx 
xxx/xxxxx 
xxxxx 
DD/MM/YY 
xx 
xxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Notes: Sort by date/visit.  
Include only subjects for whom the “None” box is not checked, i.e. only subjects with comments.