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

Overview

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.

Interventions

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

Primary outcome measures

• Overall Survival (OS) [Time frame: From the time of randomization until the date of death from any cause, assessed up to 60 months]

Secondary outcome measures (4)

• Progression-Free Survival (PFS) [Time frame: 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) [Time frame: Through study completion, with a median of 9 months]
• Incidence and nature of treatment-emergent adverse events [Time frame: Through study completion, with a median of 9 months]
• Pharmacokinetics (PK) of namodenoson in this population [Time frame: 29 days]

Eligibility criteria

Inclusion criteria

• Males and females at least 18 years of age.
• 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).
• HCC is advanced (i.e., treatment-refractory or metastatic) and no standard therapies are expected to be curative.
• HCC has progressed on at least 1, but no more than 2, prior systemic treatment regimens; prior locoregional therapy is allowed.
• Barcelona Clinic Liver Cancer (BCLC) Stage B or C (Llovet 1999).
• Prior HCC treatment was discontinued for at least 2 weeks prior to the Baseline Visit.
• Measurable disease by RECIST v1.1 (Eisenhauer 2009).
• ECOG PS of ≤ 1.
• 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).
• 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.
• Life expectancy of ≥ 6 weeks.
• For women of childbearing potential, negative serum pregnancy test result.
• Provide written informed consent to participate.
• Willing to comply with scheduled visits, treatment plans, laboratory assessments, and other trial-related procedures.

Exclusion criteria

• Receipt of >2 prior systemic drug therapies for HCC.
• 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.
• Locoregional treatment within 4 weeks prior to the Baseline Visit.
• Major surgery or radiation therapy within 4 weeks prior to the Baseline Visit.
• Use of any investigational agent within 4 weeks prior to the Baseline Visit.
• 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).
• Child-Pugh Class A, B8/9, or C cirrhosis.
• Hepatic encephalopathy.
• Occurrence of esophageal or other gastrointestinal hemorrhage requiring transfusion within 4 weeks prior to the Baseline Visit.
• Uncontrolled or clinically unstable thyroid disease, per judgment of the Principal Investigator.
• Active bacterial, viral, or fungal infection requiring systemic therapy or operative or radiological intervention.
• Known human immunodeficiency virus- or acquired immunodeficiency syndrome-related illness.
• Liver transplant.
• Active malignancy other than HCC.
• Uncontrolled arterial hypertension or congestive heart failure (New York Heart Association Classification 3 or 4).
• 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.
• 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).
• Pregnant or lactating female.
• 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.
• 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.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Romania · 10 centers

• 802 Institutul Regional de Gastroenterologie si Hepatologie — Cluj-Napoca
• 807 IOCN, Medical Oncology — Cluj-Napoca
• 809 Spitalul Clinic Judetean de Urgenta Constanta Oncology Dept — Constanța
• 801 Oncology Center "Sf. Nectarie" Medical Oncology — Craiova
• 803 Oncolab SRL — Craiova
• 805 Euroclinic lasi — Iași
• 810 IRO Iasi-Clinica Oncologie Medicala — Iași
• 808 Spitalul Clinic Pelican Oradea Oncology Department — Oradea
• … and 2 more centers

Poland · 6 centers

• Site 858 — Koszalin
• Site 852 — Krakow
• Site 857 — Mysłowice
• Site 859 — Przemyśl
• Site 855 — Warsaw
• Site 850 — Wroclaw

Bulgaria · 4 centers

• 831 Dept of Medical Oncology, Complex Oncology Ctr - Burgas EOOD — Burgas
• 835 First Department of Medical Oncology, Gastroenterology and Pulmology, Complex Oncology — Plovdiv
• Medical Center Leo Clinic EOOD Plovdiv — Plovdiv
• 834 Medical Oncology Dept, Univ Multiprofile Hospital for Active Treatment "Sv. Ivan Rilsk — Sofia

Serbia · 4 centers

• 821 Clinic for Gastroenterology and Hepatology, Military Medical Academy — Belgrade
• 822 Oncology Institute of Vojvodina — Kamenitz
• 823 Oncology Department, Health Center Kladovo — Kladovo
• 824 Univ Clin Centre Kragujevac, Dept of Oncology — Kragujevac

Bosnia and Herzegovina · 3 centers

• 841 University Clinical Centre of Republic of Srpska — Banja Luka
• 843 University Clinical Hospital Mostar — Mostar
• 842 University Clinical Centre Sarajevo — Sarajevo

Slovakia · 2 centers

• Site 867 — Banská Bystrica
• Site 865 — Košice

United States · 1 center

• Site 881 — Dallas

Israel · 1 center

• 518 Rabin Medical Center Beilinson Hospital — Petah Tikva

Moldova · 1 center

• 872 IMSP Institute of Oncology — Chisinau

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. PMID 18636149
• 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. PMID 21660967
• 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. PMID 23299770
• 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. d PMID 33430312

Identifiers

NCT: NCT05201404 · CF102-301HCC

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗