A Phase Ib/II Trial to Evaluate the Efficacy and Safety of HH-009 for the Treatment of FGF19-positive Advanced or Unresectable HCC

A Randomized, Open-Label, Multicenter, Phase Ib/II Registration Trial to Observe and Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of HH-009 Injection in FGF19-Positive Participants With Advanced or Unresectable Hepatocellular Carcinoma (HCC) Who Have Experienced Progressive Disease After Prior Systemic Therapy

This is a randomized, open-label, multicenter Phase Ib/II registration trial designed to evaluate the efficacy and safety of HH-009 in patients with FGF19-positive hepatocellular carcinoma (HCC). The study will also assess pharmacokinetics, pharmacodynamics, immunogenicity, and exploratory biomarkers.

Approximately 30 patients with FGF19-positive advanced HCC will be enrolled. Eligible participants will be randomized 1:1 to receive HH-009 at either 20 mg/kg or 30 mg/kg Q3W as monotherapy. Treatment will continue until disease progression, unacceptable toxicity, initiation of new anticancer therapy, study withdrawal, completion of two years of treatment, loss to follow-up, death, or other protocol-specified reasons, whichever occurs first.

This study is a randomized, open-label, multi-center Phase Ib/II registration clinical trial. The study aims to evaluate the efficacy and safety of HH-009 in participants with FGF19-positive HCC; meanwhile, PK, PD, and immunogenicity profiles will be analyzed, and relevant biomarkers will be explored.

Approximately 30 participants with advanced HCC who are FGF19-positive and have progressed after systemic therapy failure will be enrolled. Eligible participants meeting inclusion / exclusion criteria will be randomly assigned in a 1:1 ratio to two dose groups: HH-009 20 mg/kg or 30 mg/kg.

Eligible participants will receive HH-009 monotherapy at a dose of 20 mg/kg or 30 mg/kg according to the randomly assigned HH-009 dose group, administered once every 3 weeks (Q3W), until progressive disease, intolerable toxicity (except when tolerability is restored after dose adjustment), initiation of new anticancer therapy, loss to follow-up, death, withdrawal from the study, completion of 2 years of study treatment, or any other reason (whichever occurs first).

Inclusion Criteria:

• Voluntary participation in a clinical trial and signed informed consent.

• Ages 18 to 75 years (inclusive of the boundaries), male or female.

• Participants with advanced or unresectable HCC confirmed by pathological histology or diagnosed in accordance with the clinical criteria specified in the National Health Commission guidelines, with the following additional requirements:

  • Participants with HCC who have experienced progressive disease after prio systemic therapy;
  • Tumor tissue IHC testing for FGF19 was positive (confirmed by central laboratory);
  • Child-Pugh class A or class B (Child-Pugh score ≤7) ;
  • Barcelona Clinic Liver Cancer (BCLC) stage B or C

• ECOG score 0 or 1

• Have at least one measurable lesion according to RECIST v1.1.

• Life expectancy ≥ 12 weeks.

• Adequate organ and bone marrow function.

• Participants with HCV infection, whose HCV-RNA levels are above the lower limit of detection at the study site, are eligible if antiviral therapy is initiated prior to the first dose administration.

• Participants with hepatitis B virus (HBV) infection must have HBV DNA < 104 cps/mL or 2,000 IU/mL.

• Participants (including partners of the male participants) are willing to use effective contraception from the screening period until 6 months after the last investigational product administration.

Exclusion Criteria:

• Participated in another clinical trial of investigational drugs or investigational medical devices within 28 days prior to the first dose; or received anticancer treatment within the past 4 weeks before the first dose, or within five half-lives of the drug (whichever is shorter), including but not limited to chemotherapy, radiotherapy (allowing palliative radiotherapy completed at least two weeks prior to investigational product administration), targeted therapy, immunotherapy, or endocrine therapy; or received traditional Chinese medicine with anticancer indications within one week before the first dose.
• The previous antitumor treatment-related toxicity has not yet recovered to ≤ grade 1 or baseline level
• Previously received FGFR inhibitors, including FGFR4 inhibitors and pan-FGFR inhibitors.
• Undergone major surgery (except biopsy) within 4 weeks prior to the first study dose of the investigational product, or surgical wounds not fully healed.
• Presence of moderate to large pleural or ascitic effusion accompanied by clinical symptoms, uncontrolled, or requiring repeated drainage.
• Participants with active or a history of autoimmune diseases that are likely to recur (including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid disorders, multiple sclerosis, vasculitis, glomerulonephritis, etc.), or participants at high risk (e.g., participants who have undergone organ transplantation and require immunosuppressive therapy).
• Participants with a known history of other malignancies within 5 years prior to enrollment.
• Leptomeningeal (meningeal) metastases, active brain metastases
• Participants with known active tuberculosis or suspected active tuberculosis, or participants with active pneumonia requiring treatment.
• History of clinically significant cardiovascular and cerebrovascular diseases.
• Systemic treatment with corticosteroids or other immunosuppressive drugs within 14 days prior to the first dose.
• History of human immunodeficiency virus (HIV) infection, or active infection requiring systemic treatment for more than 7 consecutive days within 14 days prior to the first dose administration.
• Co-infection with HBV and HCV
• Blood transfusion, treatment with granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, thrombopoietin, or erythropoietin initiated within 2 weeks prior to the first dose.
• Bile acid-modulating medications that cannot be discontinued within 3 days prior to the first dose or within 5 half-lives of the drug (whichever is longer).
• History of severe allergic reactions to other therapeutic antibody drugs; or known allergy to multiple substances or suffering from severe allergic diseases.
• Pregnant or lactating females, or those with a positive blood pregnancy test.
• Other severe, acute, or chronic medical or psychiatric conditions or laboratory abnormalities that, in the investigator's judgment, may increase the risk associated with study participation or may interfere with the interpretation of study results, or any other situation considered unsuitable for participation in this study.