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

• CF102 (Drug), also known as IB-MECA: orally q12h
• Placebo (Drug), also known as Inactive pill: orally q12 hours

Primary outcomes

• 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 outcomes

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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).
• 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).
• 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).
• 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).
• 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).
• 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).

Sex: All, ages: 18 Years to any

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, ie, treatment-refractory or metastatic, and no standard therapies are expected to be curative.
4. 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).
5. Prior systemic 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).
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.

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.

Participant flow

Outcome results

• Number of Subjects With Overall Survival (Primary), Count of participants, Participants: CF102 16; Placebo Tablets of CF102 4 (p 0.536)
• Time to Progression (TTP) (Secondary), Median, Months: CF102 5.1 (1.9 to 11.2); Placebo Tablets of CF102 3.3 (1.9 to 33.2) (p .371)
• Time to Progression-Free Survival (PFS) (Secondary), Median, months: CF102 2.5 (1.8 to 6.1); Placebo Tablets of CF102 1.9 (1.8 to 3.8) (p 0.521)
• Objective Response Rate (ORR) (Secondary), Count of participants, Participants: CF102 1; Placebo Tablets of CF102 0
• Disease Control Rate (DCR) (Secondary), Count of participants, Participants: CF102 19; Placebo Tablets of CF102 10
• Summary Statistics of Laboratory Parameters Associated With Viral Hepatitis, Hepatic Dysfunction, and Cirrhosis (Secondary), Mean, U/L: CF102 47.4 +/- 29.97; Placebo Tablets of CF102 36.3 +/- 20.93 (p 0.988)
• Summary Statistics of White Blood Cell (WBC) Adenosine A3 Receptor (A3AR) Expression and Clinical Response - WBC Adenosine A3 Receptor (A3AR) Expression (Secondary), Mean, ratio of patient to healthy control: CF102 1.789 +/- 2.2103; Placebo Tablets of CF102 2.339 +/- 3.2906
• Pharmacokinetics (PK) Parameters of CF102 - CL/F (L/h) (Secondary), Geometric mean, L/h: CF102 12.42 +/- 57.83
• Pharmacokinetics (PK) Parameters of CF102 - Vc/F (L) (Secondary), Geometric mean, L: CF102 254.20 +/- 54.56
• Pharmacokinetics (PK) Parameters of CF102 - Vp/F (L) (Secondary), Geometric mean, L: CF102 49.99 +/- 16.33
• Pharmacokinetics (PK) Parameters of CF102 - Vss/F (L) (Secondary), Geometric mean, L: CF102 309.56 +/- 44.31
• Pharmacokinetics (PK) Parameters of CF102 - Elimination Half-life (Hours) (Secondary), Geometric mean, hours: CF102 18.39 +/- 29.93
• Pharmacokinetics (PK) Parameters of CF102 - AUC_0-12, Steady State (ng*h/mL) (Secondary), Geometric mean, ng*h/mL: CF102 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.

Serious adverse events by term

Other adverse events by term

• Stemmer SM, Manojlovic NS, Marinca MV, Petrov P, Cherciu N, Ganea D, Ciuleanu TE, Pusca IA, Beg MS, Purcell WT, Croitoru AE, Ilieva RN, Natosevic S, Nita AL, Kalev DN, Harpaz Z, Farbstein M, Silverman MH, Bristol D, Itzhak I, Fishman P. Namodenoson in Advanced Hepatocellular Carcinoma and Child-Pugh B Cirrhosis: Randomized Placebo-Controlled Clinical Trial. Cancers (Basel). 2021 Jan 7;13(2):187. doi: 10.3390/cancers13020187. PMID 33430312

• Study Protocol (PDF, 2018-11-06)
• Statistical Analysis Plan (PDF, 2019-08-29)

• Michael H Silverman, Study director, Can-Fite BioPharma Ltd