A Phase 2, Open-Label Study of ABSK-011 Combined Atezolizumab or SOC in HCC Patients

A Phase 2, Open-Label Study of ABSK-011 Plus Atezolizumab or Standard of Care to Assess Safety, Tolerability, Pharmacokinetics, and Anti-tumor Efficacy in Patients With Advanced or Unresectable Hepatocellular Carcinoma

This study is an open phase II clinical study, which consists of part a and Part B. Part a will evaluate the safety and tolerability of absk-011 combined with atilizumab in patients with advanced or unresectable HCC to And pk/pd characteristics, and determine the treatment plan of Part B. Part B will evaluate absk-011 combined with atilizumab Anti FGF19 overexpression in advanced stage or non resectable patients who have not received systemic therapy or only received first-line systemic therapy before In addition to the safety and tolerability of HCC subjects, the antitumor activity of the combination will be further evaluated.

Part C comprises two parts: Part C1 and Part C2. A maximum of 54 subjects with advanced or unresectable hepatocellular carcinoma (HCC) with FGF19 overexpression and no prior systemic therapy will be planned for enrollment. Eligible subjects will be prioritized for assignment to Part C2 to receive study treatment. Treatment will continue until the earliest occurrence of intolerable toxicity, disease progression, initiation of new anti-tumor therapy, withdrawal of informed consent, loss to follow-up, death, or study termination.

During part a, all subjects will receive continuous oral administration of absk-011 once a day (QD) or twice a day (bid) with an initial dose of 180 mg, and intravenous infusion (IV) of 1200 mg of atilizumab every 21 days (q3w). After the first subject (sentinel subject) in each dose cohort completed the first combined medication, follow-up subjects were administered at least 7 days later.

Part B will include subjects with advanced unresectable HCC who have not previously received systemic therapy or only received first-line systemic therapy and whose Fgf19 expression is positive. No more than 70% of the enrolled subjects have only received first-line systemic therapy

Part C1 is intended to enroll 6 subjects with advanced hepatocellular carcinoma (HCC) to receive ABSK-011 in combination with atezolizumab and bevacizumab.ABSK-011 will be administered orally at 200 mg twice daily (BID), with a single dose administered on Cycle 1 Day 1 (C1D1). The study drug should be taken with food, preferably within 30 minutes after a meal. Atezolizumab and bevacizumab will be administered in accordance with a every-3-week (Q3W) schedule.Safety and tolerability assessments will be conducted based on dose-limiting toxicities (DLTs) observed during Cycle 1 (21 days).

Part C2 is planned to enroll a maximum of 48 subjects with advanced HCC, divided into two stages:

Stage 1 of Part C2 intends to enroll 12 subjects with FGF19-overexpressing advanced HCC, who will be randomized 1:1 to two parallel treatment arms:

Arm 1: ABSK-011 plus toripalimab plus bevacizumab biosimilar Arm 2: toripalimab plus bevacizumab biosimilar ABSK-011 will be administered orally at 200 mg BID, with a single dose administered on C1D1, and taken with food, preferably within 30 minutes after a meal. All intravenous agents will be administered on a Q3W schedule.Safety and tolerability evaluations will be performed for each treatment arm based on DLTs observed during Cycle 1 (21 days).

Stage 2 of Part C2 is planned to enroll up to 36 subjects with FGF19-overexpressing advanced HCC, randomized 1:1 to Arm 1 or Arm 2, to further characterize the efficacy and safety profile of ABSK-011 in combination with standard of care (SOC).

Inclusion Criteria:

1. before implementing any program related procedures, the subjects should understand and voluntarily sign the written informed consent and indicate the date. Subjects should be able and willing to follow the study follow-up and study procedures in the protocol.
2. there is no limit on gender, and the age when signing the informed consent is ≥ 18 years old.
3. part a: subjects with advanced or unresectable HCC who must be confirmed by histology, cytology or imaging, are not suitable for curative surgery and / or local treatment, have disease progression or cannot tolerate standard treatment after standard treatment, and have no standard treatment due to physical conditions or disease status (according to local / regional guidelines), and the child Pugh score is 5-6.

Part b: subjects with advanced or unresectable HCC who must be confirmed histologically or cytologically, are not suitable for curative surgery and / or local regional treatment, and have not previously received systematic treatment or only received first-line systematic treatment-

Part C: Subjects with histologically or cytologically confirmed advanced or unresectable HCC who are not eligible for curative surgery and/or locoregional therapy and have not received prior systemic therapy, and who meet the following criteria:

1. Provide archived tumor tissue samples or undergo biopsy for FGF19 overexpression testing at the central laboratory.
2. BCLC stage B or C, Child-Pugh score 5-6, no hepatic encephalopathy, and no ascites requiring medical intervention within 7 days prior to the first dose.
3. At least 1 measurable target lesion per RECIST 1.1. For subjects who received prior locoregional therapy (e.g., transarterial (chemo)embolization, radiofrequency ablation, percutaneous injection, cryoablation, high-intensity focused ultrasound, etc.), the target lesion must not have been treated with the above locoregional therapies, or the investigator has confirmed disease progression or absence of clinical benefit in the target lesion after prior locoregional therapy.
4. Treatment with up to one cycle of a PD-1/PD-L1 inhibitor, with or without a VEGF inhibitor, prior to enrollment is permitted.

Exclusion Criteria:

1. history of autoimmune diseases
2. have a history of the second primary malignant tumor other than HCC within 5 years before screening,
3. have a history of uncorrectable electrolyte disorders that affect serum potassium, calcium or phosphorus levels.
4. meningeal metastasis or central nervous system (CNS) metastasis -