Clinical trial NCT05201404: Namodenoson in the Treatment of Advanced Hepatocellular Carcinoma in Patients With Child-Pugh Class B7 Cirrhosis
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Hepatocellular Carcinoma
Cirrhosis
Keywords: Hepatocellular carcinoma
HCC
Liver cancer
Child-Pugh Class B7 cirrhosis
CPB7
Lead sponsor: Can-Fite BioPharma
Sponsor class: INDUSTRY
First posted: 2022-01-21
Enrollment: 471
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel group, double-blinded, randomization in a 1:1 ratio to active versus placebo
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: From the time of randomization until the date of death from any cause, assessed up to 60 months
Secondary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: From the time of randomization until the date of disease progression or death from any cause, assessed up to 60 months
measure: Objective Response Rate (ORR)
timeFrame: Through study completion, with a median of 9 months
measure: Incidence and nature of treatment-emergent adverse events
timeFrame: Through study completion, with a median of 9 months
measure: Pharmacokinetics (PK) of namodenoson in this population
timeFrame: 29 days
Other outcomes:
measure: Duration Of Response (DOR)
timeFrame: Through study completion, with median of 9 months
measure: Disease Control Rate (DCR)
timeFrame: Through study completion, with median of 9 months
measure: Quality of Life (QOL) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30)
timeFrame: Through study completion, with a median of 9 months
measure: 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)
timeFrame: Through study completion, with a median of 9 months
Locations:
city: Dallas
country: United States
facility: Site 881
state: Texas
city: Banja Luka
country: Bosnia and Herzegovina
facility: 841 University Clinical Centre of Republic of Srpska
city: Mostar
country: Bosnia and Herzegovina
facility: 843 University Clinical Hospital Mostar
city: Sarajevo
country: Bosnia and Herzegovina
facility: 842 University Clinical Centre Sarajevo
city: Burgas
country: Bulgaria
facility: 831 Dept of Medical Oncology, Complex Oncology Ctr - Burgas EOOD
city: Plovdiv
country: Bulgaria
facility: 835 First Department of Medical Oncology, Gastroenterology and Pulmology, Complex Oncology Center - Plovdiv EOOD, Plovdiv
city: Plovdiv
country: Bulgaria
facility: Medical Center Leo Clinic EOOD Plovdiv
city: Sofia
country: Bulgaria
facility: 834 Medical Oncology Dept, Univ Multiprofile Hospital for Active Treatment "Sv. Ivan Rilski" EAD, Sofia
city: Petach Tikva
country: Israel
facility: 518 Rabin Medical Center Beilinson Hospital
city: Chisinau
country: Moldova, Republic of
facility: 872 IMSP Institute of Oncology
city: Koszalin
country: Poland
facility: Site 858
city: Kraków
country: Poland
facility: Site 852
city: Mysłowice
country: Poland
facility: Site 857
city: Przemyśl
country: Poland
facility: Site 859
city: Warszawa
country: Poland
facility: Site 855
city: Wroclaw
country: Poland
facility: Site 850
city: Cluj-Napoca
country: Romania
facility: 802 Institutul Regional de Gastroenterologie si Hepatologie
city: Cluj-Napoca
country: Romania
facility: 807 IOCN, Medical Oncology
city: Constanţa
country: Romania
facility: 809 Spitalul Clinic Judetean de Urgenta Constanta Oncology Dept
city: Craiova
country: Romania
facility: 801 Oncology Center "Sf. Nectarie" Medical Oncology
city: Craiova
country: Romania
facility: 803 Oncolab SRL
city: Iaşi
country: Romania
facility: 805 Euroclinic lasi
city: Iaşi
country: Romania
facility: 810 IRO Iasi-Clinica Oncologie Medicala
city: Oradea
country: Romania
facility: 808 Spitalul Clinic Pelican Oradea Oncology Department
city: Timişoara
country: Romania
facility: 804 Oncomed - Medical Oncology
city: Timişoara
country: Romania
facility: 806 Oncocenter Oncologie Clinica SRL
city: Belgrade
country: Serbia
facility: 821 Clinic for Gastroenterology and Hepatology, Military Medical Academy
city: Kladovo
country: Serbia
facility: 823 Oncology Department, Health Center Kladovo
city: Kragujevac
country: Serbia
facility: 824 Univ Clin Centre Kragujevac, Dept of Oncology
city: Sremska Kamenica
country: Serbia
facility: 822 Oncology Institute of Vojvodina
city: Banská Bystrica
country: Slovakia
facility: Site 867
city: Košice
country: Slovakia
facility: Site 865
Study officials:
affiliation: BioStrategics Consulting Ltd
name: Michael H Silverman, MD
role: STUDY_DIRECTOR
References:
citation: 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.
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.
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.
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.