Phase 2 Study of WGI-0301 Plus Nivolumab in Patients With HCC and RCC

Inclusion criteria

• 1) Age 18-75 (inclusive) on the day of singing 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 3) Subjects in each disease cohorts will need to fulfill the following criteria:

• HCC Cohort:
• Histologically or cytologically confirmed diagnosis of HCC, or clinical diagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD) criteria
• 4. Barcelona Clinic Liver Cancer (BCLC) Stage C, or BCLC Stage B that is not suitable for any curative surgeries or locoregional therapy
• Child-Pugh Liver Function Class A or Class B (score ≤ 7)
• Documented first-line standard treatment failure (disease progression or intolerance)；

• nccRCC Cohort：Histologically or cytologically confirmed diagnosis of nccRCC，that is locally advanced or with distant metastasis, and have not received any prior systemic antitumor therapy. If disease progression occurs within 6 months after the last dose of adjuvant therapy, it is considered a failure of first-line treatment and thus does not meet the criteria.
• ccRCC Cohort：Histologically or cytologically confirmed ccRCC, with locally advanced unresectable disease or distant metastasis, and disease progression or intolerance after prior first-line therapy. Patients who have received adjuvant or neoadjuvant therapy may also be screened if they meet the above criteria.

• Eligible for treatment with Nivolumab as determined by investigators according to the Package Insert and clinical judgment.

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 within 7 days prior to the first dose of study intervention 6) Life expectancy in the judgement of the Investigator > 12 weeks. 7) 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 such as radiotherapy; a new area of tumor progression within or adjacent to a previously treated lesion, if clearly measurable by a radiologist, is acceptable.

• Any adverse events (AEs) related to prior anti-tumor therapy must have resolved to ≤ Grade 1 (CTCAE v6.0). However, patients may still be screened if the investigator determines that the toxicity is well-controlled and does not affect the patient's safety or compliance with the study drug, and this has been confirmed with the sponsor.

• 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:
• For patients with no liver metastasis or lesion: AST and ALT ≤2.0× ULN, and total bilirubin ≤1.5×ULN; For patients with liver metastasis or lesion: AST and ALT ≤3.0× ULN, and total bilirubin ≤2×ULN; For patients with Gilbert Syndrome: Total bilirubin ≤3×ULN
• Serum albumin≥30g/L
• Creatinine Clearance (CrCL) ≥50 mL/min (Cockcroft-Gault formula: Ccr=(140-Age)×body weight (Kg)/72×Scr（mg/dl）{×0.85 for female subject}
• International Normalized Ratio (INR) ≤2.0 (except for patients on warfarin therapy)
• Hemeglobin≥90g/L, ANC ≥1.5×10^9/L, platelet count≥75×10^9/L (no blood transfusion, blood products, cell growth factors, albumin or any other corrective therapeutic drugs within 14 days) 11) Participants with hepatitis B virus (HBV) or hepatitis C virus (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 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: • 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 12) Women of child-bearing potential (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.

Exclusion criteria

• 1) Pregnant or breastfeeding patients or expecting to conceive or father children within the projected duration of the study 2) For the HCC Cohort, any of the following criteria：

• 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).
• Fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma or mixed hepatocellular cholangiocarcinoma；
• 3. 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) 3) Major surgery within 4 weeks prior to the first dose of study intervention. 4) Currently participating in 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) 5) 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 6) Received systemic corticosteroid (prednisone >10mg/day or equivalent) or other immunosuppressive agents within 2 weeks prior to the first dose of study intervention. Inhale or local corticosteroid, or pre-medications for infusion-related reactions/ hypersensitivity is allowed.

• Received live vaccines and live attenuated vaccines within 4 weeks prior to the first dose of study treatment, or expected to received live vaccinve or live attenuated vaccine while participating in the study 8) Previous identified allergy or hypersensitivity to components of WGI-0301 similar drugs or liposomal drugs, or Nivolumab or related excipients 9) Prior treatment with agents targeting the PI3K-AKT pathway 10) 13. 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, stroke, transient ischemic attack, pulmonary embolism, myocardial infarction, unstable angina pectoris, or left ventricular ejection fraction < 50% 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 are required for the first abnormal QTcF , and the mean value should be taken from the 3 readings. 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.

• Clinically significant bleeding risks including:
• Known hereditary or acquired bleeding or thrombotic tendencies (e.g., hereditary hemorrhagic telangiectasia or von Willebrand disease)
• History of bleeding symptoms due to esophageal or gastric varices within 6 months prior to the first dose
• Received thrombolytic agents within 10 days prior to the first dose, or currently receiving anticoagulant therapy (e.g. anticoagulant, antiplatelet) and subject 's INR and APTT are not within expected therapeutic range of anticoagulant (except sodium heparin for maintenance of central venous catheter patency) 12) Known HIV or AIDS related illness, or history of allogeneic organ transplant or allogeneic hematopoietic stem cell transplant 13) Patients with endocrine disorders that cannot be effectively controlled by hormone replacement therapy 14) Presence of active autoimmune disease requiring systemic treatment within 2 years prior to the first dose, including but not limited to: systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, etc. However, subjects with hypothyroidism, adrenal insufficiency, or pituitary insufficiency managed with hormone replacement therapy only; skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis, or alopecia); or conditions not expected to recur in the absence of external triggers are allowed.

• History of gastrointestinal perforation, gastrointestinal or non-gastrointestinal fistula, or abdominal abscess within 6 months prior to the first dose 16) Skin ulcers or severe, non-healing, or dehisced wounds within 3 months prior to the first dose 17) Known active or uncontrolled infection that may interfere with the study (e.g., active infection requiring intravenous antibiotic therapy or unexplained fever >38.5°C) 18) History of interstitial lung disease or prior non-infectious pneumonitis requiring corticosteroid treatment, or imaging findings suggestive of active pneumonia 19) History of other malignancies prior to or at study entry (except for adequately treated carcinoma in situ of the cervix, basal cell and squamous cell skin cancer, or other malignancies that have undergone curative treatment with no evidence of disease for at least 3 years).

• Pleural effusion, ascites, or pericardial effusion that are clinically symptomatic or requiring repeated drainage (as judged by the investigator) 21) Known symptomatic or untreated brain metastases, leptomeningeal metastases, or other central nervous system metastases (except for asymptomatic cases not requiring treatment).

• History of drug abuse or addiction 23) 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