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

Hepatocellular Carcinoma Clinical Trial

— LIVERATION  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05201404
• Other study ID #: CF102-301HCC
• Status: Recruiting
• Phase: Phase 3
• Start date: March 15, 2023
• Est. completion date: October 2025

Study information

• Verified date: February 2023
• Source: Can-Fite BioPharma
• Contact: Zivit Harpaz
• Phone: +972 3 924 1114
• Email: Zivit[@]canfite.co.il
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 471
• Est. completion date: October 2025
• Est. primary completion date: February 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Cirrhosis
• Fibrosis
• Hepatocellular Carcinoma
• Liver Cirrhosis

Intervention

Drug:
• Namodenoson
Adenosine A3 Receptor (A3AR) agonist
• Placebo
Control arm

Locations

Country	Name	City	State
Bosnia and Herzegovina	841 University Clinical Centre of Republic of Srpska	Banja Luka
Bosnia and Herzegovina	843 University Clinical Hospital Mostar	Mostar
Bosnia and Herzegovina	842 University Clinical Centre Sarajevo	Sarajevo
Bulgaria	831 Dept of Medical Oncology, Complex Oncology Ctr - Burgas EOOD	Burgas
Bulgaria	835 First Department of Medical Oncology, Gastroenterology and Pulmology, Complex Oncology Center - Plovdiv EOOD, Plovdiv	Plovdiv
Bulgaria	Medical Center Leo Clinic EOOD Plovdiv	Plovdiv
Bulgaria	834 Medical Oncology Dept, Univ Multiprofile Hospital for Active Treatment "Sv. Ivan Rilski" EAD, Sofia	Sofia
Israel	518 Rabin Medical Center Beilinson Hospital	Petach Tikva
Moldova, Republic of	872 IMSP Institute of Oncology	Chisinau
Poland	Site 858	Koszalin
Poland	Site 852	Kraków
Poland	Site 857	Myslowice
Poland	Site 859	Przemysl
Poland	Site 855	Warszawa
Poland	Site 850	Wroclaw
Romania	802 Institutul Regional de Gastroenterologie si Hepatologie	Cluj-Napoca
Romania	807 IOCN, Medical Oncology	Cluj-Napoca
Romania	809 Spitalul Clinic Judetean de Urgenta Constanta Oncology Dept	Constanta
Romania	801 Oncology Center "Sf. Nectarie" Medical Oncology	Craiova
Romania	803 Oncolab SRL	Craiova
Romania	805 Euroclinic lasi	Iasi
Romania	810 IRO Iasi-Clinica Oncologie Medicala	Iasi
Romania	808 Spitalul Clinic Pelican Oradea Oncology Department	Oradea
Romania	804 Oncomed - Medical Oncology	Timisoara
Romania	806 Oncocenter Oncologie Clinica SRL	Timisoara
Serbia	821 Clinic for Gastroenterology and Hepatology, Military Medical Academy	Belgrade
Serbia	823 Oncology Department, Health Center Kladovo	Kladovo
Serbia	824 Univ Clin Centre Kragujevac, Dept of Oncology	Kragujevac
Serbia	822 Oncology Institute of Vojvodina	Sremska Kamenica
Slovakia	Site 867	Banská Bystrica
Slovakia	Site 865	Košice
United States	Site 881	Dallas	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Can-Fite BioPharma

Countries where clinical trial is conducted

United States,  Bosnia and Herzegovina,  Bulgaria,  Israel,  Moldova, Republic of,  Poland,  Romania,  Serbia,  Slovakia, 

References & Publications (4)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	Pharmacokinetics (PK) of namodenoson in this population	Plasma concentration of namodenoson	29 days

External Links

•   Sponsor website