Phase 2 Study of WGI-0301 for Advanced HCC

This study will include a two-stage design: Stage 1 (dose escalation) to determine the MTD/RP2D of WGI-0301 combined with Sorafenib. Stage 2 (dose expansion) with two different dose levels of WGI-0301 in combination with standard dose Sorafenib, or standard dose Sorafenib alone.

Inclusion criteria

• ≥18 years of age on the day of signing informed consent, male or female.
• Voluntarily agree to provide signed informed consent and are willing and able to comply with all aspects of the protocol.
• Histologically or cytologically confirmed diagnosis of HCC, or clinical diagnosis of HCC as per 2018 AASLD criteria.
• BCLC Stage C or BCLC Stage B with bilobar involvement and infiltrative nature that is only suitable for systemic anti-tumor therapy, and not suitable for any curative surgeries, liver transplantation, or local therapy (BCLC Classification see Appendix 6, Section 14.6).
• Stage 1 only: At least first-line standard treatment failure (disease progression confirmed by imaging) with no available standard treatment options, or unsuitability for standard treatment, or intolerance to standard treatment.
• Stage 2 only: At least first-line standard treatment failure (disease progression confirmed by imaging) or intolerance.
• Stage 3 only: Patients must have objective radiographic disease progression or intolerance (Intolerance is defined as currently discontinued after ≥28 days of treatment due to toxicity) after only one prior line of systemic immunotherapy treatment with an anti-PD-1/ PD-L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies (Prior locoregional therapy such as surgery, radiofrequency ablation or trans-arterial chemoembolization are also allowed but not counted as systemic therapy, provided that progression has been documented after these therapies, and ≥4 weeks have elapsed since the last therapy).
• Stage 2 and Stage 3: Eligible for treatment with Sorafenib as determined by investigators according to the Package Insert and clinical judgment.
• ECOG PS of 0 or 1 within 7 days prior to the first dose of study intervention.
• Patients must have at least one measurable lesion according to RECIST 1.1 as determined by the investigator, and that has not been the target of local or regional therapy including trans-arterial chemoembolization, intra-arterial chemotherapy, ethanol, or radiofrequency ablation; a new area of tumor progression within or adjacent to a previously treated lesion, if clearly measurable by a radiologist, is acceptable.
• Life expectancy in the judgement of the Investigator > 12 weeks.
• Recovery to ≤Grade 1 (CTCAE V5.0) from toxicities related to any prior treatments unless the adverse events are clinically non-significant and/ or stable on supportive therapy, such as alopecia, Grade 2 peripheral neuropathy, and hypothyroidism stabilized on hormone replacement therapy.
• Stage 2 and Stage 3:Collection of an archived tissue sample will be requested (where available) or agree to undergo tumor tissue biopsy for biomarker testing; however, a subject will not be precluded from participating in the study if tissue sample is not available for collection or is otherwise insufficient for analysis.
• Patients must have adequate organ function as defined below:

• Child-Pugh Liver Function Class A or Class B (score ≤ 7) (see Appendix 7 in Section 14.7)
• AST and ALT ≤ 3.0 × ULN and total bilirubin ≤ 2 × ULN
• Serum albumin ≥ 2.8 g/ dL
• CrCL ≥ 40 ml/ min (Cockcroft-Gault formula: CrCL (mL/ min) = [140-age(year)] × body weight (Kg)/ [72 × Scr (mg/ dl)]{ × 0.85 for female subjects})
• INR ≤ 2.0 (except for warfarin therapy)
• Hemoglobin ≥ 8.5 g/ dL, absolute neutrophil count > 1000/ mm3, platelet count ≥ 60 000/ mm3(no blood transfusion, blood products, cell growth factors, albumin or any other corrective therapeutic drugs within 14 days)
• Participants with HBV or HCV infection will be allowed if they meet the following criteria:

• HBV-HCC: Resolved HBV infection (as evidenced by detectable HBV surface antibody, detectable HBV core antibody, undetectable HBV DNA, and undetectable HBV surface antigen) or chronic HBV infection (as evidenced by detectable HBV surface antigen or HBV DNA). Subjects with chronic HBV infection must have HBV DNA < 500 IU/ mL and must should be managed according to treatment guidelines. Those on antiviral therapy at screening should have been treated for >2 weeks before the first dose.
• HCV-HCC: Resolved HCV infection (as evidenced by detectable HCV RNA or antibody), or stable HCV infection (such as normal LFTs or being asymptomatic). Patients with positive HCV RNA requiring direct antiviral agent treatment, or those with HBV and HCV co-infection are excluded.
• WOCBP must have a negative serum pregnancy within 3 days prior to receiving the first dose of study medication and must use accepted highly effective methods of contraception from the time of signing the informed consent through 6 months after the last dose of study drug. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, or be surgically sterile, for the duration of study participation, and for 3 months after completion of study drug administration. See Appendix 1 for protocol-approved highly effective methods of contraceptive combinations.

Exclusion criteria

• Pregnant or breastfeeding patients or expecting to conceive or father children within the projected duration of the study.
• Stage 2 and Stage 3: Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.
• Complete occlusion of the major portal vein or vena cava due to HCC (The major portal vein is defined as the part of portal vein between the union of the splenic and superior mesenteric veins and the first bifurcation into the left and right vein).
• Major surgery within 4 weeks prior to the first dose of study intervention.
• Previous identified allergy or hypersensitivity to components of WGI-0301 similar drugs or liposomal drugs or related excipients.
• Stage 2 and Stage 3: Previous identified allergy or hypersensitivity to components of Sorafenib or similar drugs.
• Stage 3 only: Received prior Sorafenib therapy or any agents targeting AKT-PI3K pathway.
• Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to the first dose of study intervention (except for observational clinical trials).
• Locoregional therapy to liver within 4 weeks prior to the first dose, including but not limited to TACE, radiotherapy, radiofrequency ablation, microwave (except palliative radiotherapy for bone pain relief completed at least 2 weeks prior to the first dose).
• Small molecule targeted therapy and traditional Chinese medicine with antitumor indications received within 2 weeks prior to the first dose, or chemotherapy, biological therapy, and other antitumor treatments received within 4 weeks prior to the first dose.
• Stage 2 and Stage 3：Patients on concomitant use of strong CYP3A4 inducers (see Appendix 3 in Section 14.3) within 12 days prior to the first dose of study intervention.
• Clinically significant abnormalities of glucose metabolism (e.g., Patients with diabetes mellitus type1 or diabetes mellitus type 2 requiring treatment, or those with HbA1c ≥8.0%.
• Clinically significant cardiovascular disease including:

• Uncontrolled chronic hypertension defined as systolic > 150 mmHg or diastolic > 90 mmHg on more than one measurement despite optimal therapy (initiation or adjustment of BP medication prior to study entry is allowed provided that the average of 3 BP readings prior to enrollment is < 150/ 90 mmHg).
• Hypotension as indicated by systolic blood pressure < 90 mmHg or mean arterial pressure < 65 mmHg on 2 consecutive measurements at the Screening Visit.
• NYHA class III or IV Congestive heart failure, myocardial infarction or stroke, unstable angina pectoris, pericardial effusion (excluding trace pericardial effusion identified by echocardiography), or left ventricular ejection fraction < 45% within 6 months prior to the first dose.
• Primary cardiomyopathy (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, indeterminate cardiomyopathy).
• Bradycardia (known history of cardiovascular disease and either physical examination at rest or electrocardiogram indicating heart rate < 50 bpm), or screening ECG indicating QTcF > 470 msec, 2 retests were required for the first abnormal QTcF , and 3 mean values were taken. Or there is severe arrhythmia requiring further treatment, including but not limited to ventricular fibrillation, atrial fibrillation, sustained ventricular tachycardia, second-degree or third-degree atrioventricular block, torsades de pointes, etc.
• Stage 2 and Stage 3: Clinically significant gastrointestinal disorders including:

• Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal disease, or conditions that may hamper compliance and/ or absorption of the tested products
• Gastrointestinal perforation and/ or fistula intra-abdominal abscess or intestinal obstruction within 6 months prior to the first dose
• Clinically significant gastric bleeding within 6 months prior to the first dose (patients may be enrolled if esophageal and gastric varices are present on imaging, but no bleeding event or inpatient medical intervention occurs within 6 months prior to the first dose)
• Clinically significant bleeding risks including:

• Known hereditary or acquired bleeding or thrombotic tendencies (e.g., hereditary hemorrhagic telangiectasia or von Willebrand disease)
• Bleeding symptoms such as hemoptysis (> 1/ 2 teaspoon bright red blood) and gastrointestinal bleeding within 3 months prior to screening
• Thrombolytic agents within 10 days prior to the first dose
• Receiving anticoagulant therapy (e.g., anticoagulants, antiplatelets), and subject 's INR and APTT are not within expected therapeutic range of anticoagulant (except sodium heparin for maintenance of central venous catheter patency)
• History of solid organ transplant.
• Known HIV or AIDS related illness or is receiving systemic steroid therapy (physiological doses of hormones, such as prednisone <10 mg/day or equivalent doses of similar corticosteroids are acceptable) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.
• Known active or uncontrolled infection that could interfere with the study (such as requiring intravenous antibiotics, antiviral or antifungal medications).
• Uncontrolled ascites or pleural effusion requiring repeated drainage (Investigator 's judgment).
• Past or current history of neoplasm other than HCC, except for curatively treated nonmelanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and with no evidence of disease for at least 3 years.
• Known CNS or brain metastasis that is either symptomatic or untreated (except for asymptomatic cases not requiring treatment).
• History of drug abuse or addiction at the present stage.
• Subject has any other conditions or reason that, in the opinion of the Investigator, interferes with the ability of the subject to participate in the trial, places the subject at undue risk or complicates the interpretation of data.