A Phase II Study of GV20-0251 in Combination With Anti-PD-1 Monoclonal Antibodies in Patients With Unresectable, Locally Advanced, or Metastatic Solid Tumors.

Inclusion criteria

• Voluntarily signed written informed consent (ICF) prior to any study-specific procedures.
• Able and willing to participate in and comply with study procedures throughout the study.
• Age ≥ 18 and ≤ 80 years, any gender.
• Histologically confirmed unresectable, locally advanced, or metastatic solid tumor.
• Must have failed standard of care (SOC), be intolerant to SOC, or be deemed by the investigator to be unsuitable for a specific form of SOC. If SOC failure, documented progression from SOC is required.
• No more than 2 prior lines of systemic therapy. Subjects with more lines may be enrolled after sponsor approval. Treatment-naive subjects with locally advanced or metastatic melanoma who have not received systemic therapy may enroll.
• Tumor types include: endometrial cancer, cervical cancer, ovarian cancer, triple-negative breast cancer, prostate cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, hepatocellular carcinoma (HCC), biliary tract malignancies (including only intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer; excluding ampullary carcinoma), pMMR/MSS colorectal adenocarcinoma, pancreatic ductal adenocarcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, and melanoma (assessed per local institutional standard practice).
• For certain tumor types, IGSF8 protein expression on the tumor cell membrane must be positive at pre-screening or screening.
• If the subject has received prior anti-PD-1/PD-L1 therapy, documented disease progression during treatment with anti-PD-1/PD-L1 monoclonal antibody (as monotherapy or combined with other checkpoint inhibitors/therapies) is required.
• Eligible subjects of childbearing potential (female and male) must agree to use effective contraception (hormonal or barrier method) starting 28 days prior to the first dose of GV20-0251, throughout the treatment period, and for at least 4 months after the last dose.
• Must have at least one measurable lesion per RECIST v1.1. Previously irradiated lesions with documented progression may be considered measurable.
• Must provide archival tumor tissue collected within 3 years prior to signing the ICF. If archival tissue is >3 years old, enrollment requires medical confirmation with the sponsor.
• ECOG performance status of 0-1 prior to the first dose on C1D1.
• Expected survival ≥ 24 weeks.
• No history of other primary malignancies, except: (a) a curatively treated malignancy with no active disease for at least 2 years prior to consent and low risk of subsequent relapse; or (b) curatively treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or carcinoma in situ of the breast.
• Adequate organ, Hepatic, and Coagulation function at screening.
• All adverse events related to prior anticancer therapy have resolved to ≤ Grade 1 (per NCI CTCAE v5.0). For persistent Grade 2 toxicities deemed by the investigator unlikely to resolve, eligibility may be discussed with the sponsor.
• For HCC or biliary tract malignancy subjects only, as Child-Pugh Class A.

Exclusion criteria

• Prior immunotherapy discontinued due to ≥ Grade 3 immune-related adverse events (irAEs) - except endocrine disorders manageable with replacement therapy or asymptomatic elevated serum amylase/lipase - Grade 2 myocarditis, or recurrent Grade 2 pneumonitis.
• Insufficient washout period from prior systemic anticancer therapy before initiating GV20-0251 and anti-PD-1 therapy (C1D1)
• Received radiotherapy within 2 weeks prior to initiating GV20-0251 and anti-PD-1 therapy, or has radiation-related toxicity requiring corticosteroids. For NSCLC subjects: pulmonary radiotherapy > 30 Gy within 6 months prior to C1D1.
• Currently enrolled in a drug or device clinical trial; or received an investigational device or investigational drug within 4 weeks prior to C1D1.
• Diagnosed with immunodeficiency; or currently receiving chronic systemic corticosteroids (> 10 mg/day prednisone equivalent) or any other form of immunosuppressive therapy.
• History of gastrointestinal perforation and/or fistula within 6 months prior to consent; or active gastric/duodenal ulcer, ulcerative colitis, or other GI conditions the investigator believes may cause bleeding or perforation.
• Clinically significant and/or uncontrolled cardiac disease, including NYHA Class III or IV heart failure, uncontrolled hypertension (systolic BP > 160 mmHg), clinically significant arrhythmia assessed by the investigator to affect study participation safety, or myocardial infarction within 6 months prior to C1D1.
• Severe hypersensitivity reaction (≥ Grade 3) to anti-PD-1 monoclonal antibody and/or any of its excipients; or prior severe hypersensitivity to biologic therapies that the investigator considers may increase subject risk.
• Acute leukemia or chronic lymphocytic leukemia (CLL).
• QTcF > 470 msec, or history of congenital long QT syndrome, or clinically significant ECG abnormalities (including pericarditis) that the investigator considers may affect subject safety.
• Active infection requiring systemic treatment; or active, uncontrolled bacterial, viral, or fungal infection requiring systemic treatment within 7 days prior to C1D1.
• History of (non-infectious) pneumonitis/interstitial lung disease requiring steroid treatment, or current pneumonitis/interstitial lung disease.
• Active autoimmune disease requiring systemic treatment within 2 years prior to C1D1
• HIV infection.
• Active HBV or HCV infection
• Prior major organ transplantation
• Prior autologous or allogeneic bone marrow transplantation.
• Symptomatic primary CNS malignancy, CNS metastases, or leptomeningeal disease.
• Major surgery (excluding diagnostic procedures) or severe trauma within 28 days prior to the first dose of GV20-0251, or currently in recovery that the investigator deems would interfere with the study, or anticipated major surgery during the study.
• Received a live or attenuated vaccine within 30 days prior to the first dose.
• Requires treatment with interferon-α or related/similar agents within 3 weeks prior to C1D1 or during the entire study period.
• Requires more than one paracentesis per 8 weeks to manage ascites; or single ascites drainage volume > 1.5 liters within 8 weeks prior to C1D1.
• Psychiatric illness or substance abuse disorder (e.g., drug abuse, alcohol dependence) that may interfere with the subject's ability to comply with study requirements.
• Other serious non-malignant conditions or laboratory abnormalities that, in the opinion of the investigator and/or sponsor, make the subject unsuitable for the study; or other circumstances that the investigator believes may confound study results or prevent the subject from completing the study.
• Additional exclusion criteria that applicable to HCC or biliary tract malignancy subjects.