Namodenoson in the Treatment of Advanced Hepatocellular Carcinoma in Patients With Child-Pugh Class B7 Cirrhosis (LIVERATION)

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Namodenoson in the Treatment of Advanced Hepatocellular Carcinoma in Patients With Child-Pugh Class B7 Cirrhosis

This is a clinical trial in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh Class B7 (CPB7) cirrhosis whose disease has progressed on at least 1st-line therapy. The trial will evaluate the efficacy and safety of namodenoson as compared to placebo.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma; Cirrhosis
• Intervention / Treatment: Drug: Namodenoson; Drug: Placebo

Detailed Description

This is a multicenter, randomized, double-blind, placebo-controlled clinical trial in patients with advanced HCC and CPB7 cirrhosis whose disease has progressed on at least 1st-line therapy. The trial will evaluate the efficacy and safety of namodenoson as compared to placebo. Patients will be randomly assigned in a 2:1 ratio to treatment with oral doses of either namodenoson 25 mg or matching placebo administered twice daily for consecutive 28-day cycles. Patients will be evaluated regularly for safety. Tumor imaging will be performed every two cycles. Treatment will continue until the patient experiences PD or unacceptable drug-related intolerability. Patients will return for a follow-up visit 28 days after completion of the last dose of study drug, and survival data will be obtained for all randomized patients who consent to long-term follow-up. Patients who discontinue dosing and consent to follow-up will be followed indefinitely for survival status.

Once the requisite number of events has been observed and the blind is broken for analysis of the trial results, any surviving patients who remain on blinded drug will be offered the opportunity to continue dosing with OL namodenoson 25 mg twice daily indefinitely.

• Study Type: Interventional
• Enrollment (Estimated): 471
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Zivit Harpaz; Phone Number: +972 3 924 1114; Email: Zivit@canfite.co.il

Study Locations

• Bosnia and Herzegovina
  • Banja Luka, Bosnia and Herzegovina
    • Not yet recruiting
    • 841 University Clinical Centre of Republic of Srpska
    • Contact: Study Coordinator
  • Mostar, Bosnia and Herzegovina
    • Not yet recruiting
    • 843 University Clinical Hospital Mostar
    • Contact: Study Coordinator
  • Sarajevo, Bosnia and Herzegovina
    • Not yet recruiting
    • 842 University Clinical Centre Sarajevo
    • Contact: Study Coordinator
• Bulgaria
  • Burgas, Bulgaria
    • Not yet recruiting
    • 831 Dept of Medical Oncology, Complex Oncology Ctr - Burgas EOOD
    • Contact: Study Coordinator
  • Plovdiv, Bulgaria
    • Not yet recruiting
    • 835 First Department of Medical Oncology, Gastroenterology and Pulmology, Complex Oncology Center - Plovdiv EOOD, Plovdiv
    • Contact: Study Coordinator
  • Plovdiv, Bulgaria
    • Not yet recruiting
    • Medical Center Leo Clinic EOOD Plovdiv
    • Contact: Study Coordinator
  • Sofia, Bulgaria
    • Recruiting
    • 834 Medical Oncology Dept, Univ Multiprofile Hospital for Active Treatment "Sv. Ivan Rilski" EAD, Sofia
    • Contact: Study Coordinator
• Israel
  • Petach Tikva, Israel
    • Recruiting
    • 518 Rabin Medical Center Beilinson Hospital
    • Contact: Salomon Stemmer, MD
• Moldova, Republic of
  • Chisinau, Moldova, Republic of
    • Recruiting
    • 872 IMSP Institute of Oncology
    • Contact: Study Coordinator
• Poland
  • Koszalin, Poland
    • Not yet recruiting
    • Site 858
    • Contact: Study Coordinator
  • Kraków, Poland
    • Not yet recruiting
    • Site 852
    • Contact: Study Coordinator
  • Mysłowice, Poland
    • Not yet recruiting
    • Site 857
    • Contact: Study Coordinator
  • Przemyśl, Poland
    • Not yet recruiting
    • Site 859
    • Contact: Study Coordinator
  • Warszawa, Poland
    • Not yet recruiting
    • Site 855
    • Contact: Study Coordinator
  • Wroclaw, Poland
    • Not yet recruiting
    • Site 850
    • Contact: Study Coordinator
• Romania
  • Cluj-Napoca, Romania
    • Recruiting
    • 802 Institutul Regional de Gastroenterologie si Hepatologie
    • Contact: Study Coordinator
  • Cluj-Napoca, Romania
    • Not yet recruiting
    • 807 IOCN, Medical Oncology
    • Contact: Study Coordinator
  • Constanţa, Romania
    • Not yet recruiting
    • 809 Spitalul Clinic Judetean de Urgenta Constanta Oncology Dept
    • Contact: Study Coordinator
  • Craiova, Romania
    • Recruiting
    • 801 Oncology Center "Sf. Nectarie" Medical Oncology
    • Contact: Study Coordinator
  • Craiova, Romania
    • Recruiting
    • 803 Oncolab SRL
    • Contact: Study Coordinator
  • Iaşi, Romania
    • Recruiting
    • 805 Euroclinic lasi
    • Contact: Study Coordinator
  • Iaşi, Romania
    • Recruiting
    • 810 IRO Iasi-Clinica Oncologie Medicala
    • Contact: Study Coordinator
  • Oradea, Romania
    • Recruiting
    • 808 Spitalul Clinic Pelican Oradea Oncology Department
    • Contact: Study Coordinator
  • Timişoara, Romania
    • Recruiting
    • 804 Oncomed - Medical Oncology
    • Contact: Study Coordinator
  • Timişoara, Romania
    • Recruiting
    • 806 Oncocenter Oncologie Clinica SRL
    • Contact: Study Coordinator
• Serbia
  • Belgrade, Serbia
    • Not yet recruiting
    • 821 Clinic for Gastroenterology and Hepatology, Military Medical Academy
    • Contact: Study Coordinator
  • Kladovo, Serbia
    • Not yet recruiting
    • 823 Oncology Department, Health Center Kladovo
    • Contact: Study Coordinator
  • Kragujevac, Serbia
    • Not yet recruiting
    • 824 Univ Clin Centre Kragujevac, Dept of Oncology
    • Contact: Study Coordinator
  • Sremska Kamenica, Serbia
    • Not yet recruiting
    • 822 Oncology Institute of Vojvodina
    • Contact: Study Coordinator
• Slovakia
  • Banská Bystrica, Slovakia
    • Not yet recruiting
    • Site 867
    • Contact: Study Coordinator
  • Košice, Slovakia
    • Not yet recruiting
    • Site 865
    • Contact: Study Coordinator
• United States
  • Texas
    • Dallas, Texas, United States, 75201
      • Not yet recruiting
      • Site 881
      • Contact: Study Coordinator

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Males and females at least 18 years of age.

2. Diagnosis of HCC:

   • For patients without cirrhosis at the time of diagnosis, histologic confirmation is required (archival tissue is acceptable).
   • For patients with underlying cirrhosis at the time of diagnosis, diagnosis of HCC established according to the American Association for the Study of Liver Diseases Practice Guideline algorithm (Marrero 2018).
3. HCC is advanced (i.e., treatment-refractory or metastatic) and no standard therapies are expected to be curative.
4. HCC has progressed on at least 1, but no more than 2, prior systemic treatment regimens; prior locoregional therapy is allowed.
5. Barcelona Clinic Liver Cancer (BCLC) Stage B or C (Llovet 1999).
6. Prior HCC treatment was discontinued for at least 2 weeks prior to the Baseline Visit.
7. Measurable disease by RECIST v1.1 (Eisenhauer 2009).
8. ECOG PS of ≤ 1.
9. Cirrhosis classified as CPB7; if ascites is used as a scoring criterion, it must be classified as Grade ≥2 by the Clinical Practice Guidelines of the European Association for the Study of the Liver (EASL 2010).

10. The following laboratory values must be documented within ten days prior to the first dose of study drug:

    • Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
    • Platelet count at least 75 × 10^9/L
    • Creatinine clearance at least 50 mg/dL (estimated glomerular filtration rate by the Cockcroft-Gault or the Modification of Diet in Renal Disease methods)
    • AST and ALT ≤ 5 × the upper limit of normal (ULN)
    • Total bilirubin ≤ 3.0 mg/dL
    • Serum albumin ≥ 2.8 g/dL.
11. Life expectancy of ≥ 6 weeks.
12. For women of childbearing potential, negative serum pregnancy test result.
13. Provide written informed consent to participate.
14. Willing to comply with scheduled visits, treatment plans, laboratory assessments, and other trial-related procedures.

Exclusion Criteria:

1. Receipt of >2 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. Locoregional treatment within 4 weeks prior to the Baseline Visit.
4. Major surgery or radiation therapy within 4 weeks prior to the Baseline Visit.
5. Use of any investigational agent within 4 weeks prior to the Baseline Visit.
6. Concomitant use of P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP) inhibitors and/or substrates with a narrow therapeutic index unless the medication can be taken at least 3 hours before or after taking the investigational product (see Section 12.2).
7. Child-Pugh Class A, B8/9, or C cirrhosis.
8. Hepatic encephalopathy.
9. Occurrence of esophageal or other gastrointestinal hemorrhage requiring transfusion within 4 weeks prior to the Baseline Visit.
10. Uncontrolled or clinically unstable thyroid disease, per judgment of the Principal Investigator.
11. Active bacterial, viral, or fungal infection requiring systemic therapy or operative or radiological intervention.
12. Known human immunodeficiency virus- or acquired immunodeficiency syndrome-related illness.
13. Liver transplant.
14. Active malignancy other than HCC.
15. Uncontrolled arterial hypertension or congestive heart failure (New York Heart Association Classification 3 or 4).
16. 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.
17. History of, or ongoing, cardiac dysrhythmias requiring treatment, atrial fibrillation of any grade, or persistent prolongation of the QTc (Fridericia) interval to > 470 msec (patients with bundle branch block will not be excluded for QTc reasons).
18. Pregnant or lactating female.
19. 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 patient's circumstances while on study drug.
20. 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.
21. 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 patient inappropriate for entry into this trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Namodenoson (CF102); Namodenoson 25 mg orally BID, until disease progression or unacceptable adverse events	Drug: Namodenoson; Adenosine A3 Receptor (A3AR) agonist; Other Names: CF102
Placebo Comparator: Placebo; Matching placebo orally BID, until disease progression or unacceptable adverse events	Drug: Placebo; Control arm; Other Names: Inactive control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Median duration of survival	From the time of randomization until the date of death from any cause, assessed up to 60 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Median time to disease progression using RECIST and modified RECIST criteria	From the time of randomization until the date of disease progression or death from any cause, assessed up to 60 months
Objective Response Rate (ORR)	Proportion of patients who experience Objective Response (OR) using RECIST and modified RECIST criteria	Through study completion, with a median of 9 months
Incidence and nature of treatment-emergent adverse events	Incidence and nature of treatment-emergent adverse events as assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5)	Through study completion, with a median of 9 months
Pharmacokinetics (PK) of namodenoson in this population	Plasma concentration of namodenoson	29 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration Of Response (DOR)	Time from first response (CR or PR) to progression or death, whichever occurs first	Through study completion, with median of 9 months
Disease Control Rate (DCR)	Proportion of patients who experience OR as well as those who experience Stable Disease (SD) for at least four treatment cycles, ie, four months	Through study completion, with median of 9 months
Quality of Life (QOL) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30)	Assess QOL in this population using the EORTC QLQ-C30, a 30-item questionnaire. Each question is measured in a range in score from 0 to 100. A high scale score represents a higher response level.	Through study completion, with a median of 9 months
Quality of Life (QOL), using the hepatocellular carcinoma- (HCC-) specific module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Hepatocellular Carcinoma 18-question Module (EORTC QLQ-HCC18)	Assess QOL in this population using the HCC-specific module of the EORTC QLQ-HCC18, an 18-item questionnaire. Each question is measured in a range in score from 0 to 100. A high scale score represents a higher response level.	Through study completion, with a median of 9 months

Collaborators and Investigators

• Sponsor: Can-Fite BioPharma
• Investigators: Study Director: Michael H Silverman, MD, BioStrategics Consulting Ltd

Publications and helpful links

General Publications

• Bar-Yehuda S, Stemmer SM, Madi L, Castel D, Ochaion A, Cohen S, Barer F, Zabutti A, Perez-Liz G, Del Valle L, Fishman P. The A3 adenosine receptor agonist CF102 induces apoptosis of hepatocellular carcinoma via de-regulation of the Wnt and NF-kappaB signal transduction pathways. Int J Oncol. 2008 Aug;33(2):287-95.
• Cohen S, Stemmer SM, Zozulya G, Ochaion A, Patoka R, Barer F, Bar-Yehuda S, Rath-Wolfson L, Jacobson KA, Fishman P. CF102 an A3 adenosine receptor agonist mediates anti-tumor and anti-inflammatory effects in the liver. J Cell Physiol. 2011 Sep;226(9):2438-47. doi: 10.1002/jcp.22593.
• Stemmer SM, Benjaminov O, Medalia G, Ciuraru NB, Silverman MH, Bar-Yehuda S, Fishman S, Harpaz Z, Farbstein M, Cohen S, Patoka R, Singer B, Kerns WD, Fishman P. CF102 for the treatment of hepatocellular carcinoma: a phase I/II, open-label, dose-escalation study. Oncologist. 2013;18(1):25-6. doi: 10.1634/theoncologist.2012-0211. Epub 2013 Jan 8.
• 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.

Helpful Links

• Sponsor website

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2023
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: December 21, 2021
• First Submitted That Met QC Criteria: January 7, 2022
• First Posted (Actual): January 21, 2022

Study Record Updates

• Last Update Posted (Estimated): June 16, 2023
• Last Update Submitted That Met QC Criteria: June 15, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: HCC; Hepatocellular carcinoma; Liver cancer; Child-Pugh Class B7 cirrhosis; CPB7
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Fibrosis; Carcinoma; Carcinoma, Hepatocellular; Liver Cirrhosis
• Other Study ID Numbers: CF102-301HCC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No