Overview

This is a randomized, double-blind, multicenter, Phase 2 study to evaluate the efficacy and safety of ABSK-011 plus BSC versus placebo plus BSC in advanced or unresectable hepatocellular carcinoma (HCC) patients with FGF19 overexpression who have received prior systemic therapy. Approximately 141 advanced or unresectable HCC patients with FGF19 overexpression who have received prior systemic therapy will be enrolled and randomized to experimental arm or control arm in a 2:1 ratio. Patients will receive assigned study treatment, every 28-day treatment cycle within 1 day of randomization until disease progression, intolerable toxicity, start of new anti-tumor therapy, death, patient refuse to continue treatment, loss to follow-up, or other reasons leading to treatment discontinuation. Immediate BICR review is required for patients with radiographic disease progression as assessed by the investigator. If disease progression is assessed by BICR, the investigator is allowed to unblind after disease progression according to the protocol-specified procedures. After unblinding, patients in the experimental arm, study drug should be discontinued. Patients in the control arm may be transferred to receive ABSK-011 plus BSC after assessment.

Eligibility

Inclusion Criteria:

1. Patients should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed. Patients should be able and willing to comply with study visits and procedures as per protocol.
2. Patients (male or female) ≥ 18 years of age at the time of signing the informed consent form.
3. Patients with advanced or unresectable HCC confirmed histologically/cytologically or clinically according to the American Association for the Study of Liver Diseases (AASLD) criteria (for patients with cirrhosis).
4. Have received at least one prior PD- (L) 1 inhibitor approved as a single agent or in combination for the treatment of HCC and at least one mTKI approved for the treatment of HCC.
5. BCLC stage B(ineligible for local or radical therapy, or relapse or progression of disease after local therapy or radical therapy) or C.
6. Child-Pugh class A.
7. Positive for FGF19 overexpression.
8. At least 1 measurable lesion meeting RECIST v1.1 criteria.
9. ECOG performance status 0 or 1.
10. Life expectancy ≥ 3 months.
11. Adequate control of blood pressure (BP) at screening.
12. Adequate organ function and bone marrow function.
13. Non-surgically sterilized male or female patients of childbearing potential must agree to use reliable contraception for at least 2 weeks prior to randomization until 1 month after the last dose of study treatment.

Exclusion Criteria:

1. Known allergies or hypersensitivity to any component of the investigational product (ABSK-011 or placebo).
2. Previous treatment with selective FGFR4 inhibitors.
3. Known fibrolamellar HCC, sarcomatous HCC, or mixed hepatocellular carcinoma-cholangiocarcinoma.
4. Previous anti-tumor therapy is ≤ 4 weeks from randomization.
5. Major surgery within 4 weeks prior to randomization; or any surgical wound infection, dehiscence, or incomplete healing within 2 weeks prior to randomization; Or major surgery is planned during study treatment.
6. History of second primary malignancies other than HCC within the first 5 years of screening.
7. Liver tumors as a percentage of whole liver ≥ 50% as judged by the investigator.
8. Toxicities caused by prior chemotherapy, radiotherapy, and other anti-tumor therapies (including immunotherapy) did not recover to ≤ Grade 1 CTCAE v5.0.
9. Imaging revealed HCC involving the main portal vein (Vp4), inferior vena cava, superior vena cava, superior mesenteric vein, or heart.
10. Impaired cardiac function or clinically important heart disease.
11. Patients coinfected with HBV and HCV.
12. Known acquired immunodeficiency syndrome (AIDS) -associated disease or tested positive for HIV 1/2 antibodies.
13. Active or documented gastrointestinal bleeding within 6 months prior to screening.
14. Patients with intractable/uncontrolled pleural or pericardial effusion requiring intervention within 2 weeks prior to randomization and clinically significant ascites.
15. Prior or current hepatic encephalopathy (any grade).
16. Presence of meningeal or central nervous system (CNS) metastases.
17. Previous organ transplant and anti-rejection drug therapy indicated.
18. The factors that significantly affect the absorption of oral drugs.
19. Receipt of P-gp transporter inhibitors or moderate, strong inhibitors or inducers of CYP3A4 within 2 weeks prior to randomization.
20. Any serious acute or chronic infection requiring systemic antibacterial, antifungal, or antiviral therapy within 2 weeks prior to randomization.
21. Patient who cannot be assessed by contrast-enhanced CT and/or MRI due to allergy to computed tomography (CT) and/or magnetic resonance imaging (MRI) contrast media or other contraindications.
22. Any other clinically significant comorbidities may affect the patient's health or safety, affect the signing of informed consent, affect protocol compliance, or interfere with the interpretation of the study results.