Phase 2, Randomized, Double-Blind, Placebo-Controlled of the Efficacy and Safety of CF102 in Hepatocellular Carcinoma (HCC)

• Sponsor: Can-Fite BioPharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02128958
• Collaborator: (none)
• Enrollment: 78
• Locations: 21
• Arms: 2
• Actual Duration (Months): 88
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Drug: CF102; Drug: Placebo	Phase 2

Detailed Description

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 78 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study in the Second-Line Treatment of Advanced Hepatocellular Carcinoma in Subjects With Child-Pugh Class B Cirrhosis
• Actual Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: Nov 27, 2017
• Actual Study Completion Date: Dec 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CF102 orally q12h	Drug: CF102; orally q12h; Other Names: IB-MECA
Placebo Comparator: Placebo tablets of CF102 orally q12h	Drug: Placebo; orally q12 hours; Other Names: Inactive pill

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Overall Survival [From date of first treatment (Cycle 1 Day 1) until date of death from any cause, assessed up to 12 months]

   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. Overall Survival is defined as the time from Baseline (Cycle 1 Day 1) to death due to any cause, calculated as (date of death- date of Cycle 1 Day 1) +1.OS will be summarized in months, which will be obtained by dividing OS in days by 30 days/month. Summary statistics will be determined using the Kaplan-Meier (KM) estimate of the survival function and the between-treatment comparison will be performed using the logrank test as the primary analysis.

Secondary Outcome Measures

1. Time to Progression (TTP) [From date of first treatment (Cycle 1 Day 1) until the date of first documented progression, assessed up to 36 months]

   Time to Progression (TTP) is the time from Baseline to the first Overall Response of Progressive Disease (PD), calculated as date of first PD - date of Cycle 1 Day 1+1. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. TTP will be summarized in months, which will be obtained by dividing TTP in days by 30 days/month. Summary statistics will be determined using the KM estimate of the survival function for TTP. The between-treatment comparison will be performed using the logrank test.

2. Time to Progression-Free Survival (PFS) [From date of first treatment (Cycle 1 Day 1) until the date of first documented disease progression or date of death, which occurred first, assessed up to 36 months]

   Time to Progression-Free Survival (PFS) is the time from Baseline to the first Overall Response of Progressive Disease (PD) or death due to any cause if the subject dies without experiencing PD, calculated as date of first PD or date of death - date of Cycle 1 Day 1+1. PFS will be summarized in months, which will be obtained by dividing PFS in days by 30 days/month. Summary statistics will be determined using the KM estimate of the survival function for PFS. The between-treatment comparison will be performed using the logrank test.

3. Objective Response Rate (ORR) [The end of even-numbered cycles (Cycle 3 Day 1,Cycle 5 Day 1,Cycle 7 Day 1, Cycle 9 Day 1, Cycle 11 Day 1) assessed up to 12 months]

   Objective Response Rate (ORR) is assessed as the percentage of subjects who achieved a Complete Response (CR) or Partial Response (PR). Per RECIST criteria v1.1, CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm; PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Overall Response is the sum of subjects achieving CR or PR.

4. Disease Control Rate (DCR) [The end of even-numbered cycles (Cycle 3 Day 1,Cycle 5 Day 1,Cycle 7 Day 1, Cycle 9 Day 1, Cycle 11 Day 1) assessed up to 12 months]

   Disease Control Rate (DCR) is assessed as the percentage of subjects who achieved a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) using RECIST criteria. Per RECIST criteria v1.1, CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm; PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm) taking as reference the smallest sum diameters while on study.

5. Summary Statistics of Laboratory Parameters Associated With Viral Hepatitis, Hepatic Dysfunction, and Cirrhosis [Baseline (Cycle 1 Day 1); Cycle 11 Day 15]

   The raw and change from baseline (CFB) for each laboratory parameter (alanine aminotransferase (ALT), albumin, aspartate aminotransferase (AST), bilirubin (direct and total), International Normalized Ratio (INR),and prothrombin time (PT)) will be summarized by treatment and visit. CFB is calculated as (Value at Post-Baseline visit - Value at Baseline). The baseline value used in the calculations of CFB is the value taken at Cycle 1 Day 1.

6. Summary Statistics of White Blood Cell (WBC) Adenosine A3 Receptor (A3AR) Expression and Clinical Response - WBC Adenosine A3 Receptor (A3AR) Expression [Baseline (Cycle 1 Day 1) and Cycle 11 Day 1]

   Summary statistics for WBC adenosine A3 receptor (A3AR) expression and CFB in WBC A3AR expression will be provided by treatment and visit. A3AR mRNA expression in WBC was determined from blood collected to a PAXgene RNA tubes (Qiagen, Venlo, The Netherlands), using the QuantiGene Plex 2.0® assay (Thermo Fisher, Waltham, MA, USA). β-actin was used as a reference control, and the oligonucleotide probe sets were designed by Thermo Fisher. Luminescence from each specific probe set was captured by Glomax Multi (Promega, Madison, WI, USA). A3AR was expressed in units, where 1 unit was defined as the mean of A3AR expression in healthy subjects (n = 50). Healthy subjects were 20-70 years of age with no known illness and no prior treatment.

7. Pharmacokinetics (PK) Parameters of CF102 - CL/F (L/h) [Cycle 1 Days 1, 8 and 15; Cycle 2 day 1]

   Describe the PK parameter CL/F (L/h) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).

8. Pharmacokinetics (PK) Parameters of CF102 - Vc/F (L) [Cycle 1 Days 1, 8 and 15; Cycle 2 day 1]

   Describe the PK parameter Vc/F (L) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).

9. Pharmacokinetics (PK) Parameters of CF102 - Vp/F (L) [Cycle 1 Days 1, 8 and 15; Cycle 2 day 1]

   Describe the PK parameter Vp/F (L) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).

10. Pharmacokinetics (PK) Parameters of CF102 - Vss/F (L) [Cycle 1 Days 1, 8 and 15; Cycle 2 day 1]

    Describe the PK parameter Vss/F (L) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).

11. Pharmacokinetics (PK) Parameters of CF102 - Elimination Half-life (Hours) [Cycle 1 Days 1, 8 and 15; Cycle 2 day 1]

    Describe the PK parameter Elimination half-life (hours) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).

12. Pharmacokinetics (PK) Parameters of CF102 - AUC_0-12, Steady State (ng*h/mL) [Cycle 1 Days 1, 8 and 15; Cycle 2 day 1]

    Describe the PK parameter AUC_0-12, steady state (ng*h/mL) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

1. HCC is advanced, ie, treatment-refractory or metastatic, and no standard therapies are expected to be curative.

2. Receipt of 1 previous systemic drug therapy for at least 3 weeks and withdrawal from treatment due either to intolerability or to radiographic 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).

3. Prior systemic treatment was discontinued for at least 2 weeks prior to the Baseline Visit.

4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2 (Appendix B).

5. Cirrhosis classified as Child-Pugh Class B (Appendix C).

6. 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.

1. Life expectancy of ≥ 6 weeks.

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. Active bacterial, viral, or fungal infection requiring systemic therapy or operative or radiological intervention.

10. Known human immunodeficiency virus- or acquired immunodeficiency syndrome-related illness.

11. Liver transplant.

12. Active malignancy other than HCC.

13. Uncontrolled arterial hypertension or congestive heart failure (New York Heart Association Classification 3 or 4) (Appendix B).

14. 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.

15. 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.

16. Pregnant or lactating female.

17. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
2	Simmons Cancer Center	Dallas	Texas	United States	75390
3	Complex Oncology Center - Plovdiv	Plovdiv		Bulgaria
4	Multiprofile Hospital for Active Treatment Central Onco Hospita	Plovdiv		Bulgaria
5	Multiprofile Hospital for Active Treatment "Tokuda Hospital Sofia" AD	Sofia		Bulgaria
6	Multiprofile Hospital for Active Treatment for women's health - Nadezhda	Sofia		Bulgaria
7	Multiprofile Hospital for Active Treatment Serdica	Sofia		Bulgaria
8	Multiprofile Hospital for Active Treatment "Sveta Marina" EAD	Varna		Bulgaria
9	Rabin Medical Center	Petach Tikva		Israel
10	Institutul Clinic Fundeni - Sectia Oncologie Medicala	Bucuresti		Romania
11	Clinica Bendis - Oncologie Medicala	Cluj		Romania
12	Centrul de Oncologie ONCOLAB	Craiova		Romania
13	Institutul Regional de Oncologie Iasi - Sectia Oncologie Medicala	Iaşi		Romania
14	Spitalul Pelican Impex SRL- Sectia Oncologie Medicala	Oradea		Romania
15	SC DACMED SRL - Oncologie	Ploieşti		Romania
16	Spitalului Clinic Judetean de Urgenta - Sectia Oncologie Medicala	Sibiu		Romania
17	Spitalul Judetean de Urgenta "Sf. Ioan Cel Nou" - sectia Oncologie Medicala	Suceava		Romania
18	Vojnomedicinska Akademija Beograd	Belgrade		Serbia
19	Zdravstveni Centar Kladovo Služba Onkologije	Kladovo		Serbia
20	Klinički Centar Niš Klinika za Onkologiju	Niš		Serbia
21	Institut za Onkologiju Vojvodine	Sremska Kamenica		Serbia

Sponsors and Collaborators

• Can-Fite BioPharma

Investigators

• Study Director: Michael H Silverman, Can-Fite BioPharma Ltd

Study Documents (Full-Text)

• Study Protocol - Nov 6, 2018
• Statistical Analysis Plan - Aug 29, 2019

More Information

Publications

None provided.

• Responsible Party: Can-Fite BioPharma
• ClinicalTrials.gov Identifier: NCT02128958
• Other Study ID Numbers: CF102-201HCC
• First Posted: May 1, 2014
• Last Update Posted: Mar 9, 2022
• Last Verified: Mar 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Can-Fite BioPharma: Hepatocellular Carcinoma; Child-Pugh Class B Cirrhosis
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular

Study Results

Participant Flow

Arm/Group Title	CF102	Placebo Tablets of CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID	Placebo capsules administered orally BID
Period Title: Overall Study
STARTED	50	28
COMPLETED	29	18
NOT COMPLETED	21	10

Baseline Characteristics

Arm/Group Title	CF102	Placebo Tablets of CF102	Total
Arm/Group Description	CF102 25 mg capsules administered orally BID	Placebo capsules administered orally BID	Total of all reporting groups
Overall Participants	50	28	78
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.4 (11.64)	65.2 (10.22)	63.4 (11.17)
Sex: Female, Male (Count of Participants)
Female	12 24%	9 32.1%	21 26.9%
Male	38 76%	19 67.9%	57 73.1%
Race/Ethnicity, Customized (Count of Participants)
White/Caucasian	48 96%	27 96.4%	75 96.2%
Black/African	1 2%	0 0%	1 1.3%
Oriental	0 0%	1 3.6%	1 1.3%
Other	1 2%	0 0%	1 1.3%
Diagnostic Procedure (Count of Participants)
Cytology/Histology	27 54%	17 60.7%	44 56.4%
American Association for the Study of Liver Diseases	23 46%	11 39.3%	34 43.6%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Overall Survival
Description	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. Overall Survival is defined as the time from Baseline (Cycle 1 Day 1) to death due to any cause, calculated as (date of death- date of Cycle 1 Day 1) +1.OS will be summarized in months, which will be obtained by dividing OS in days by 30 days/month. Summary statistics will be determined using the Kaplan-Meier (KM) estimate of the survival function and the between-treatment comparison will be performed using the logrank test as the primary analysis.
Time Frame	From date of first treatment (Cycle 1 Day 1) until date of death from any cause, assessed up to 12 months

Outcome Measure Data

Analysis Population Description

The analysis of the primary outcome measure was performed on the Intent-To-Treat (ITT) Population, defined as all subjects who received at least one dose of study medication (i.e., Safety Population) with any post-Baseline assessment recorded. Exclusion of subjects from the ITT Population was determined prior to unblinding.

Arm/Group Title	CF102	Placebo Tablets of CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID	Placebo capsules administered orally BID
Measure Participants	50	28
12-month Survival - Yes	16 32%	4 14.3%
12-month Survival - No	34 68%	24 85.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CF102, Placebo Tablets of CF102
	Comments	The between-treatment comparison (CF102 vs Placebo) of Overall Survival will be performed using the log rank test as the primary analysis.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.536
	Comments
	Method	Log Rank
	Comments

2. Secondary Outcome

Title	Time to Progression (TTP)
Description	Time to Progression (TTP) is the time from Baseline to the first Overall Response of Progressive Disease (PD), calculated as date of first PD - date of Cycle 1 Day 1+1. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. TTP will be summarized in months, which will be obtained by dividing TTP in days by 30 days/month. Summary statistics will be determined using the KM estimate of the survival function for TTP. The between-treatment comparison will be performed using the logrank test.
Time Frame	From date of first treatment (Cycle 1 Day 1) until the date of first documented progression, assessed up to 36 months

Outcome Measure Data

Analysis Population Description

The analysis of the secondary outcome measure was performed on the Intent-To-Treat (ITT) Population, defined as all subjects who received at least one dose of study medication (i.e., Safety Population) with any post-Baseline assessment recorded. Exclusion of subjects from the ITT Population was determined prior to unblinding.

Arm/Group Title	CF102	Placebo Tablets of CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID	Placebo capsules administered orally BID
Measure Participants	50	28
Median (Inter-Quartile Range) [Months]	5.1	3.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CF102, Placebo Tablets of CF102
	Comments	The between-treatment comparison (CF102 vs Placebo) of Time to Progression will be performed using the log rank test as the primary analysis.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	.371
	Comments
	Method	Log Rank
	Comments

3. Secondary Outcome

Title	Time to Progression-Free Survival (PFS)
Description	Time to Progression-Free Survival (PFS) is the time from Baseline to the first Overall Response of Progressive Disease (PD) or death due to any cause if the subject dies without experiencing PD, calculated as date of first PD or date of death - date of Cycle 1 Day 1+1. PFS will be summarized in months, which will be obtained by dividing PFS in days by 30 days/month. Summary statistics will be determined using the KM estimate of the survival function for PFS. The between-treatment comparison will be performed using the logrank test.
Time Frame	From date of first treatment (Cycle 1 Day 1) until the date of first documented disease progression or date of death, which occurred first, assessed up to 36 months

Outcome Measure Data

Analysis Population Description

The analysis of the secondary outcome measure was performed on the Intent-To-Treat (ITT) Population, defined as all subjects who received at least one dose of study medication (i.e., Safety Population) with any post-Baseline assessment recorded. Exclusion of subjects from the ITT Population was determined prior to unblinding.

Arm/Group Title	CF102	Placebo Tablets of CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID	Placebo capsules administered orally BID
Measure Participants	50	28
Median (Inter-Quartile Range) [months]	2.5	1.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CF102, Placebo Tablets of CF102
	Comments	The between-treatment comparison (CF102 vs Placebo) will be performed on Time to Progression Free Survival using the logrank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.521
	Comments
	Method	Log Rank
	Comments

4. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	Objective Response Rate (ORR) is assessed as the percentage of subjects who achieved a Complete Response (CR) or Partial Response (PR). Per RECIST criteria v1.1, CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm; PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Overall Response is the sum of subjects achieving CR or PR.
Time Frame	The end of even-numbered cycles (Cycle 3 Day 1,Cycle 5 Day 1,Cycle 7 Day 1, Cycle 9 Day 1, Cycle 11 Day 1) assessed up to 12 months

Outcome Measure Data

Analysis Population Description

The analysis of the secondary outcome measure was performed on the Intent-To-Treat (ITT) Population, defined as all subjects who received at least one dose of study medication (i.e., Safety Population) with any post-Baseline assessment recorded. Exclusion of subjects from the ITT Population was determined prior to unblinding.

Arm/Group Title	CF102	Placebo Tablets of CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID	Placebo capsules administered orally BID
Measure Participants	50	28
Cycle 3 Day 1	1 2%	0 0%
Cycle 5 Day 1	2 4%	0 0%
Cycle 7 Day 1	2 4%	0 0%
Cycle 9 Day 1	2 4%	0 0%
Cycle 11 Day 1	2 4%	0 0%

5. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	Disease Control Rate (DCR) is assessed as the percentage of subjects who achieved a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) using RECIST criteria. Per RECIST criteria v1.1, CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm; PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm) taking as reference the smallest sum diameters while on study.
Time Frame	The end of even-numbered cycles (Cycle 3 Day 1,Cycle 5 Day 1,Cycle 7 Day 1, Cycle 9 Day 1, Cycle 11 Day 1) assessed up to 12 months

Outcome Measure Data

Analysis Population Description

The analysis of the secondary outcome measure was performed on the Intent-To-Treat (ITT) Population, defined as all subjects who received at least one dose of study medication (i.e., Safety Population) with any post-Baseline assessment recorded. Exclusion of subjects from the ITT Population was determined prior to unblinding.

Arm/Group Title	CF102	Placebo Tablets of CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID	Placebo capsules administered orally BID
Measure Participants	50	28
Cycle 3 Day 1	19 38%	10 35.7%
Cycle 5 Day 1	9 18%	2 7.1%
Cycle 7 Day 1	7 14%	2 7.1%
Cycle 9 Day 1	5 10%	2 7.1%
Cycle 11 Day 1	4 8%	1 3.6%

6. Secondary Outcome

Title	Summary Statistics of Laboratory Parameters Associated With Viral Hepatitis, Hepatic Dysfunction, and Cirrhosis
Description	The raw and change from baseline (CFB) for each laboratory parameter (alanine aminotransferase (ALT), albumin, aspartate aminotransferase (AST), bilirubin (direct and total), International Normalized Ratio (INR),and prothrombin time (PT)) will be summarized by treatment and visit. CFB is calculated as (Value at Post-Baseline visit - Value at Baseline). The baseline value used in the calculations of CFB is the value taken at Cycle 1 Day 1.
Time Frame	Baseline (Cycle 1 Day 1); Cycle 11 Day 15

Outcome Measure Data

Analysis Population Description

The analysis of the secondary outcome measure was performed on the Intent-To-Treat (ITT) Population, defined as all subjects who received at least one dose of study medication (i.e., Safety Population) with any post-Baseline assessment recorded. Exclusion of subjects from the ITT Population was determined prior to unblinding.

Arm/Group Title	CF102	Placebo Tablets of CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID	Placebo capsules administered orally BID
Measure Participants	50	28
ALT - Pre-Study	47.4 (29.97)	36.3 (20.93)
ALT - Cycle 1 Day 1	46.5 (25.60)	35.7 (26.75)
ALT - Cycle 11 Day 15	55.0 (45.39)	44.0 (45.23)
ALT - CFB to Cycle 11 Day 15	7.2 (43.73)	10.0 (23.17)
AST - Pre-Study	83.8 (50.36)	64.5 (38.49)
AST - Cycle 1 Day 1	88.8 (58.88)	66.7 (40.84)
AST - Cycle 11 Day 15	77.1 (57.5)	46.5 (23.90)
AST - CFB to Cycle 11 Day 15	7.4 (46.34)	8.3 (23.21)
Albumin - Pre-Study	32.8 (4.97)	33.7 (5.44)
Albumin - Cycle 1 Day 1	32.4 (5.21)	32.9 (5.50)
Albumin - Cycle 11 Day 15	36.5 (3.88)	35.8 (4.27)
Albumin - CFB to Cycle 11 Day 15	2.2 (5.17)	-0.8 (8.85)
Bilirubin (Direct) - Pre-Study	9.0 (7.33)	5.4 (3.32)
Bilirubin (Direct) - Cycle 1 Day 1	9.6 (9.00)	5.3 (3.71)
Bilirubin (Direct) - Cycle 11 Day 15	4.2 (2.39)	3.3 (0.96)
Bilirubin (Direct) - CFB to Cycle 11 Day 15	-0.7 (3.16)	1.3 (2.5)
Bilirubin (Total) - Pre-Study	20.5 (12.9)	14.9 (6.39)
Bilirubin (Total) - Cycle 1 Day 1	21.1 (15.94)	15.1 (9.62)
Bilirubin (Total) - Cycle 11 Day 15	14.3 (4.10)	9.8 (2.87)
Bilirubin (Total) - CFB to Cycle 11 Day 15	0.7 (5.41)	2.0 (3.56)
Prothrombin Time (PT) - Pre-Study	12.39 (1.85)	12.08 (1.097)
PT - Cycle 1 Day 1	12.17 (1.37)	12.30 (1.33)
PT - Cycle 11 Day 15	11.82 (1.128)	11.70 (0.942)
PT - CFB to Cycle 11 Day 15	0.08 (0.657)	0.53 (1.212)
International Normalized Ratio (INR) - Pre-Study	1.19 (0.176)	1.15 (0.114)
INR - Cycle 1 Day 1	1.17 (0.141)	1.19 (0.138)
INR - Cycle 11 Day 15	1.11 (0.105)	1.13 (0.096)
INR - CFB to Cycle 11 Day 15	-0.01 (0.078)	0.05 (0.129)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CF102, Placebo Tablets of CF102
	Comments	Between-treatment comparisons of ALT will be performed at Cycle 11 Day 15 using ANCOVA with CFB as the dependent variable and the Baseline value of the variable as the covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.988
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CF102, Placebo Tablets of CF102
	Comments	Between-treatment comparisons of AST will be performed at Cycle 11 Day 15 using ANCOVA with CFB as the dependent variable and the Baseline value of the variable as the covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.989
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	CF102, Placebo Tablets of CF102
	Comments	Between-treatment comparisons of Albumin will be performed at Cycle 11 Day 15 using ANCOVA with CFB as the dependent variable and the Baseline value of the variable as the covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.717
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	CF102, Placebo Tablets of CF102
	Comments	Between-treatment comparisons of Bilirubin (direct) will be performed at Cycle 11 Day 15 using ANCOVA with CFB as the dependent variable and the Baseline value of the variable as the covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.891
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	CF102, Placebo Tablets of CF102
	Comments	Between-treatment comparisons of Bilirubin (Total) will be performed at Cycle 11 Day 15 using ANCOVA with CFB as the dependent variable and the Baseline value of the variable as the covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.275
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	CF102, Placebo Tablets of CF102
	Comments	Between-treatment comparisons of PT will be performed at Cycle 11 Day 15 using ANCOVA with CFB as the dependent variable and the Baseline value of the variable as the covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.549
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	CF102, Placebo Tablets of CF102
	Comments	Between-treatment comparisons of INR will be performed at Cycle 11 Day 15 using ANCOVA with CFB as the dependent variable and the Baseline value of the variable as the covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.479
	Comments
	Method	ANCOVA
	Comments

7. Secondary Outcome

Title	Summary Statistics of White Blood Cell (WBC) Adenosine A3 Receptor (A3AR) Expression and Clinical Response - WBC Adenosine A3 Receptor (A3AR) Expression
Description	Summary statistics for WBC adenosine A3 receptor (A3AR) expression and CFB in WBC A3AR expression will be provided by treatment and visit. A3AR mRNA expression in WBC was determined from blood collected to a PAXgene RNA tubes (Qiagen, Venlo, The Netherlands), using the QuantiGene Plex 2.0® assay (Thermo Fisher, Waltham, MA, USA). β-actin was used as a reference control, and the oligonucleotide probe sets were designed by Thermo Fisher. Luminescence from each specific probe set was captured by Glomax Multi (Promega, Madison, WI, USA). A3AR was expressed in units, where 1 unit was defined as the mean of A3AR expression in healthy subjects (n = 50). Healthy subjects were 20-70 years of age with no known illness and no prior treatment.
Time Frame	Baseline (Cycle 1 Day 1) and Cycle 11 Day 1

Outcome Measure Data

Analysis Population Description

The analysis of the secondary outcome measure was performed using data from selected study sites on subjects in the Intent-To-Treat (ITT) Population, defined as all subjects who received at least one dose of study medication (i.e., Safety Population) with any post-Baseline assessment recorded. Exclusion of subjects from the ITT Population was determined prior to unblinding. The selection of study sites for participation in the A3AR blood sampling was determined according to the protocol.

Arm/Group Title	CF102	Placebo Tablets of CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID	Placebo capsules administered orally BID
Measure Participants	32	20
Baseline - Cycle 1 Day 1	1.789 (2.2103)	2.339 (3.2906)
Cycle 11 Day 1	2.821 (3.8114)	1.1 (0.0849)
CFB to Cycle 11 Day 1	0.757 (0.7948)	-0.3 (0.5798)

8. Secondary Outcome

Title	Pharmacokinetics (PK) Parameters of CF102 - CL/F (L/h)
Description	Describe the PK parameter CL/F (L/h) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).
Time Frame	Cycle 1 Days 1, 8 and 15; Cycle 2 day 1

Outcome Measure Data

Analysis Population Description

The PK analysis was conducted on advanced hepatocellular carcinoma patients with Child Pugh class B cirrhosis who received 25 mg BID for 29 days.

Arm/Group Title	CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID
Measure Participants	45
Geometric Mean (Geometric Coefficient of Variation) [L/h]	12.42 (57.83)

9. Secondary Outcome

Title	Pharmacokinetics (PK) Parameters of CF102 - Vc/F (L)
Description	Describe the PK parameter Vc/F (L) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).
Time Frame	Cycle 1 Days 1, 8 and 15; Cycle 2 day 1

Outcome Measure Data

Analysis Population Description

The PK analysis was conducted on advanced hepatocellular carcinoma patients with Child Pugh class B cirrhosis who received 25 mg BID for 29 days.

Arm/Group Title	CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID
Measure Participants	45
Geometric Mean (Geometric Coefficient of Variation) [L]	254.20 (54.56)

10. Secondary Outcome

Title	Pharmacokinetics (PK) Parameters of CF102 - Vp/F (L)
Description	Describe the PK parameter Vp/F (L) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).
Time Frame	Cycle 1 Days 1, 8 and 15; Cycle 2 day 1

Outcome Measure Data

Analysis Population Description

The PK analysis was conducted on advanced hepatocellular carcinoma patients with Child Pugh class B cirrhosis who received 25 mg BID for 29 days.

Arm/Group Title	CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID
Measure Participants	45
Geometric Mean (Geometric Coefficient of Variation) [L]	49.99 (16.33)

11. Secondary Outcome

Title	Pharmacokinetics (PK) Parameters of CF102 - Vss/F (L)
Description	Describe the PK parameter Vss/F (L) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).
Time Frame	Cycle 1 Days 1, 8 and 15; Cycle 2 day 1

Outcome Measure Data

Analysis Population Description

The PK analysis was conducted on advanced hepatocellular carcinoma patients with Child Pugh class B cirrhosis who received 25 mg BID for 29 days.

Arm/Group Title	CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID
Measure Participants	45
Geometric Mean (Geometric Coefficient of Variation) [L]	309.56 (44.31)

12. Secondary Outcome

Title	Pharmacokinetics (PK) Parameters of CF102 - Elimination Half-life (Hours)
Description	Describe the PK parameter Elimination half-life (hours) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).
Time Frame	Cycle 1 Days 1, 8 and 15; Cycle 2 day 1

Outcome Measure Data

Analysis Population Description

The PK analysis was conducted on advanced hepatocellular carcinoma patients with Child Pugh class B cirrhosis who received 25 mg BID for 29 days.

Arm/Group Title	CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID
Measure Participants	45
Geometric Mean (Geometric Coefficient of Variation) [hours]	18.39 (29.93)

13. Secondary Outcome

Title	Pharmacokinetics (PK) Parameters of CF102 - AUC_0-12, Steady State (ng*h/mL)
Description	Describe the PK parameter AUC_0-12, steady state (ng*h/mL) of namodenoson in subjects with Child-Pugh Class B cirrhosis who received twice daily administration of namodenoson for 29 days in Study CF102-201HCC at Day 1 and Day 29. In order to use a model-based Bayesian analysis in these subjects, a population PK (PPK) model of namodenoson had to be first created with the rich namodenoson concentration data available from two previously conducted studies (healthy volunteers in CF102-101 receiving single doses of 1 to 40 mg; and advanced hepatocellular carcinoma patients in CF102-102HCC receiving 1 to 25 mg BID of namodenoson for 29 days).
Time Frame	Cycle 1 Days 1, 8 and 15; Cycle 2 day 1

Outcome Measure Data

Analysis Population Description

The PK analysis was conducted on advanced hepatocellular carcinoma patients with Child Pugh class B cirrhosis who received 25 mg BID for 29 days.

Arm/Group Title	CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID
Measure Participants	45
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	2012.54 (57.83)

Adverse Events

Time Frame	AEs were recorded for each subject at the start of Cycle 1 Day 1 visit and followed to the 28-day Follow-Up Visit (28 days post End of Dosing) for up to 1 year/ Open-Label (OL) Follow-Up Visit (28 days post OL End of Dosing) for an average of 1 year. For observed toxicity thought to be at least possibly related to study drug was not resolved by the 28-day Follow-Up Visit/OL Follow-Up Visit, the subject was followed until the event resolved or stabilized, for an average of up to 24 months.
Adverse Event Reporting Description	Serious adverse event classification based on the FDA regulatory definition of a serious AE.
Arm/Group Title	CF102		Placebo Tablets of CF102
Arm/Group Description	CF102 25 mg capsules administered orally BID		Placebo capsules administered orally BID
All Cause Mortality
	CF102		Placebo Tablets of CF102
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/50 (68%)		24/28 (85.7%)
Serious Adverse Events
	CF102		Placebo Tablets of CF102
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/50 (74%)		20/28 (71.4%)
Blood and lymphatic system disorders
Anaemia	0/50 (0%)		1/28 (3.6%)
Cardiac disorders
Cardiac failure	1/50 (2%)		0/28 (0%)
Myocardial infarction	0/50 (0%)		1/28 (3.6%)
Cardio-respiratory arrest	2/50 (4%)		1/28 (3.6%)
Gastrointestinal disorders
Subileus	1/50 (2%)		0/28 (0%)
Abdominal adhesions	1/50 (2%)		0/28 (0%)
Gastrointestinal haemorrhage	4/50 (8%)		0/28 (0%)
Ascites	2/50 (4%)		1/28 (3.6%)
Peritoneal haemorrhage	1/50 (2%)		0/28 (0%)
Oesophageal varices haemorrhage	0/50 (0%)		1/28 (3.6%)
Abdominal Pain	1/50 (2%)		0/28 (0%)
General disorders
Multiple organ dysfunction syndrome	0/50 (0%)		1/28 (3.6%)
Death	1/50 (2%)		0/28 (0%)
Disease Progression	13/50 (26%)		5/28 (17.9%)
Chest pain	0/50 (0%)		1/28 (3.6%)
Hepatobiliary disorders
Hyperbilirubinaemia	1/50 (2%)		0/28 (0%)
Hepatic failure	0/50 (0%)		2/28 (7.1%)
Hepatic cirrhosis	1/50 (2%)		0/28 (0%)
Infections and infestations
Bronchitis	0/50 (0%)		1/28 (3.6%)
Cellulitis	1/50 (2%)		0/28 (0%)
Sepsis	1/50 (2%)		0/28 (0%)
Investigations
Hepatic enzyme increased/	1/50 (2%)		0/28 (0%)
Aspartate aminotransferase increased	1/50 (2%)		0/28 (0%)
Bilirubin conjugated increased	0/50 (0%)		1/28 (3.6%)
Metabolism and nutrition disorders
Hypoglycaemia	1/50 (2%)		0/28 (0%)
Hyponatraemia	1/50 (2%)		0/28 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma	5/50 (10%)		2/28 (7.1%)
Malignant neoplasm progression/	1/50 (2%)		1/28 (3.6%)
Metastases to lung	0/50 (0%)		1/28 (3.6%)
Nervous system disorders
Coma	0/50 (0%)		1/28 (3.6%)
Encephalopathy	1/50 (2%)		0/28 (0%)
Hepatic Encephalopathy	3/50 (6%)		1/28 (3.6%)
Ischaemic stroke	1/50 (2%)		0/28 (0%)
Renal and urinary disorders
Renal failure	0/50 (0%)		1/28 (3.6%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/50 (0%)		1/28 (3.6%)
Dyspnoea	0/50 (0%)		1/28 (3.6%)
Acute respiratory failure	1/50 (2%)		0/28 (0%)
Pleural effusion	1/50 (2%)		1/28 (3.6%)
Vascular disorders
Vena cava thrombosis	1/50 (2%)		0/28 (0%)
Subclavian vein thrombosis	0/50 (0%)		1/28 (3.6%)
Superior vena cava occlusion	0/50 (0%)		1/28 (3.6%)
Other (Not Including Serious) Adverse Events
	CF102		Placebo Tablets of CF102
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/50 (92%)		26/28 (92.9%)
Blood and lymphatic system disorders
Anaemia	8/50 (16%)		5/28 (17.9%)
Gastrointestinal disorders
Abdominal Pain	9/50 (18%)		3/28 (10.7%)
Ascites	10/50 (20%)		2/28 (7.1%)
Constipation	0/50 (0%)		2/28 (7.1%)
Diarrhoea	2/50 (4%)		2/28 (7.1%)
Gastrointestinal haemorrhage	4/50 (8%)		0/28 (0%)
Nausea	9/50 (18%)		6/28 (21.4%)
Vomiting	3/50 (6%)		4/28 (14.3%)
General disorders
Asthenia	7/50 (14%)		6/28 (21.4%)
Chest pain	2/50 (4%)		3/28 (10.7%)
Disease Progression	14/50 (28%)		5/28 (17.9%)
Fatigue	9/50 (18%)		3/28 (10.7%)
Oedema peripheral	10/50 (20%)		5/28 (17.9%)
Pain	2/50 (4%)		2/28 (7.1%)
Pyrexia	3/50 (6%)		2/28 (7.1%)
Hepatobiliary disorders
Hepatic failure	0/50 (0%)		2/28 (7.1%)
Hyperbilirubinaemia	4/50 (8%)		0/28 (0%)
Investigations
Alanine aminotransferase increased	2/50 (4%)		2/28 (7.1%)
Aspartate aminotransferase increased	6/50 (12%)		2/28 (7.1%)
Blood alkaline phosphatase increased	0/50 (0%)		2/28 (7.1%)
Blood bilirubin increased	0/50 (0%)		3/28 (10.7%)
Blood thyroid stimulating hormone increased	1/50 (2%)		3/28 (10.7%)
Tri-iodothyronine free decreased	0/50 (0%)		2/28 (7.1%)
Weight decreased	4/50 (8%)		4/28 (14.3%)
Weight increased	4/50 (8%)		3/28 (10.7%)
Metabolism and nutrition disorders
Decreased appetite	4/50 (8%)		1/28 (3.6%)
Hyperkalaemia	2/50 (4%)		2/28 (7.1%)
Hypoalbuminaemia	4/50 (8%)		2/28 (7.1%)
Hypoglycaemia	3/50 (6%)		0/28 (0%)
Hyponatraemia	2/50 (4%)		3/28 (10.7%)
Musculoskeletal and connective tissue disorders
Back pain	3/50 (6%)		1/28 (3.6%)
Pain in extremity	1/50 (2%)		3/28 (10.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma	5/50 (10%)		2/28 (7.1%)
Nervous system disorders
Dizziness	3/50 (6%)		2/28 (7.1%)
Headache	3/50 (6%)		1/28 (3.6%)
Hepatic encephalopathy	3/50 (6%)		1/28 (3.6%)
Respiratory, thoracic and mediastinal disorders
Cough	4/50 (8%)		3/28 (10.7%)
Dyspnoea	3/50 (6%)		2/28 (7.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.