A Phase 2 Study in the Second-Line Treatment of Advanced Hepatocellular Carcinoma in Subjects With Child-Pugh Class B Cirrhosis
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Sponsor: Can-Fite BioPharma

 
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 
Confidential 
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 
Confidential 
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 
Confidential 
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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Protocol CF102-201HCC, Amendment 5 
Confidential 
6 November 2018 
 
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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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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
238
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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
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
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).
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
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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245

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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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18. Scher H, Halabi S, Tannock I, et al. Design and end points of
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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 
 
 

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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 
 
 

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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) 
 
 

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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)