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

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.

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.

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.