A Clinical Study of GO321 in Patients With Advanced Solid Tumors

This study adopts a single-arm, open-label, dose-escalation design to investigate the safety, tolerability, and preliminary efficacy of GO321 recombinant oncolytic virus injection via intratumoral or intracavitary administration in patients with advanced solid tumors progressing after standard-of-care (SOC) therapy. The trial consists of two parts: a single-dose escalation phase and a multiple-dose expansion phase.

Part 1: Single-Dose Escalation The primary Objectives: To evaluate the safety and tolerability of single intratumoral or intracavitary GO321 injection at varying dose levels in SOC-refractory advanced solid tumor patients, and identify the Recommended Dose (RD) of intratumoral/intracavitary administration for Phase 2..

The secondary Objectives: 1) To evaluate the pharmacokinetic (PK) profile and viral shedding of GO321 following single intratumoral/intracavitary administration; 2) To evaluate the preliminary efficacy of GO321; 3) To evaluate the immunogenicity of GO321; 4) To monitor peripheral blood pharmacodynamic immunological markers related to T-lymphocyte subsets and changes in plasma cytokines (as applicable).

The exploratory Objectives: To assess changes in genomic or proteomic profiles in tumor tissue or peripheral blood (as applicable).

Part 2: Multiple-Dose Expansion The Main Objectives is to evaluate the safety and tolerability of multiple intratumoral (or intracavitary) injections of GO321 at the RD level in SOC-refractory advanced solid tumor patients, and determine the optimal dosing regimen.

The secondary Objectives: 1) To evaluate the pharmacokinetic (PK) profile and viral shedding of GO321 following multiple intratumoral/intracavitary administrations; 2) To evaluate the preliminary efficacy of GO321; 3) To evaluate the immunogenicity of GO321; 4) To monitor peripheral blood pharmacodynamic immunological markers related to T-lymphocyte subsets and changes in plasma cytokines (as applicable).

The exploratory Objectives: To assess changes in genomic or proteomic profiles in tumor tissue or peripheral blood (as applicable).

Inclusion criteria

• Age 18 years old and above, regardless of gender.
• Histologically or cytologically confirmed advanced malignant solid tumors that are refractory to or have failed standard therapy (including disease progression and/or intolerance to toxicity), or for which no standard therapy is available.
• For patients with malignant ascites secondary to malignant tumors (e.g., ovarian cancer, gastrointestinal solid malignancies) who are planned to receive intracavitary injection, the following criteria must be met:

• a. Malignant ascites is determined by the investigator to be caused by cancer cell dissemination, and not complicated by ascites due to other etiologies;
• b. Recurrence of ≥ Grade 2 ascites within 4 weeks after at least one prior local therapy (including paracentesis, intraperitoneal chemotherapy, peritoneovenous shunt, hyperthermic intraperitoneal chemotherapy, etc.);
• c. Large-volume peritoneal effusion confirmed by computed tomography (CT) or ultrasound, with a clinical indication for local therapeutic intervention targeting the ascites.
• Patients scheduled for intratumoral injection must meet the following requirements: At least one evaluable lesion confirmed by local imaging per RECIST v1.1 that is amenable to intratumoral injection. A lesion suitable for intratumoral injection (with or without CT/ultrasound guidance) is defined as a palpable mass or a mass visible by CT/ultrasound that can be injected under CT/ultrasound guidance, located in the skin, subcutaneous tissue, or deep-seated regions, with a longest diameter ≥ 1.0 cm (or short axis ≥ 1.5 cm if a lymph node), and deemed appropriate for intratumoral injection by the investigator. If the injection site has been previously irradiated, eligibility may be considered after discussion with the sponsor.
• Eastern Cooperative Oncology Group (ECOG) score ≤2.
• Expected survival time ≥3 months.
• Study participants had adequate organ function at screening/baseline, and the laboratory indicators met the following criteria:

• a. Hematopoietic system (no previous blood transfusion or hematopoietic stimulating factor therapy within 14 days) : absolute neutrophil count (ANC) ≥1.5E+09/L; Hemoglobin (Hgb) ≥90g/L; Platelet count (Plt) ≥75E+09/L.
• b. Liver function: serum total bilirubin (TBIL) ≤1.5×ULN, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3×ULN, with liver metastasis TBIL≤3×ULN, ALT and AST≤5×ULN; Serum albumin ≥2.8 g/dL (Subjects may receive albumin supplementation to meet these laboratory criteria).
• c. Renal function: serum creatinine (Cr) ≤1.5×ULN or creatinine clearance (according to Cockroft-Gault formula) >50mL/min.
• d. Coagulation: international normalized ratio (INR) ≤1.5, activated partial thromboplastin time (APTT) ≤1.5×ULN.
• Study participants were willing and able to comply with protocol requirements for the duration of the trial, including but not limited to receiving treatment, use effective contraception throughout trial participation and for 6 months after the last study drug administration, and undergoing regular follow-up and examinations.

Exclusion criteria

• Female participants who were pregnant or lactating.
• Presence of another malignancy within the previous 2 years, except for cancers with a low risk of metastasis and death (5-year survival rate, >90%), such as adequately treated basal-cell or squamous-cell skin cancer or carcinoma in situ of the cervix and other cancers in situ.
• Adverse events from prior anti-tumor therapy have not recovered to Grade ≤ 1 per CTCAE v6.0, or to the levels specified in the inclusion/exclusion criteria (with the exception of alopecia, skin hyperpigmentation, or other toxicities deemed by the investigator to have no safety risk). Participants with chronic Grade 2 toxicity may be eligible after discussion with the sponsor, provided the toxicity is asymptomatic or adequately controlled with stable medications.
• Received nitrosoureas or mitomycin C within 6 weeks prior to the first dose of the investigational product; received oral fluoropyrimidines or small-molecule targeted agents within 2 weeks or 5 half-lives (whichever is longer) prior to the first dose; received traditional Chinese herbal medicines or proprietary Chinese medicines with anti-tumor indications within 2 weeks prior to the first dose; received other systemic anti-tumor therapies, including chemotherapy, radiotherapy, biotherapy, endocrine therapy, immunotherapy, etc., within 3 weeks or 5 half-lives (whichever is shorter) prior to the first dose.
• Presence of any of the following infections or diseases:

• a. Active hepatitis B (HBsAg positive and/or HBcAb positive with an HBV DNA test value greater than the upper limit of normal); Active hepatitis C (anti-HCV antibody positive for further HCV RNA positive).
• b. A known history of immunodeficiency virus (HIV) disease or HIV antibody positive or active syphilis.
• c. Evidence of clinically significant immunodeficiency such as a primary immunodeficiency state such as severe combined immunodeficiency (SCID); Opportunistic bacterial infection.
• Have a history of active autoimmune disease requiring systemic therapy such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc., or have been receiving long-term systemic steroids (prednisone >10 mg/ day or equivalent dose of the same drug) or any other form of immunosuppressive therapy within 14 days before the first use of the investigational drug. The following patients are NOT excluded:

• a. Subjects with clinically stable autoimmune thyroid disease
• b. Patients receiving topical/inhaled corticosteroids (ocular, intra-articular, intranasal formulations)
• c. Short-course glucocorticoids (≤3 days) used prophylactically (e.g., contrast allergy prevention)
• d. Patients receiving physiological hormone replacement doses.
• Received allogeneic tissue or solid organ transplantation.
• A history of severe cardiovascular and cerebrovascular disease, including but not limited to:

• a. New York Heart Association (NYHA) class ≥II congestive heart failure.
• b. left ventricular ejection fraction (LVEF) <50%.
• c. QT interval corrected with Fridericia's method (QTcF) >470 ms or syndrome of prolonged QT interval.
• d. Acute coronary syndrome, aortic dissection, major arrhythmia, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events occurred within 6 months before the first dose.
• e. Presence of uncontrolled hypertension despite treatment (systolic BP>160 mmHg or diastolic BP>100 mmHg, as judged by the investigator).
• f. Occurrence of Grade ≥ 3 bleeding events within 6 months prior to the first dose; or current presence of > Grade 2 bleeding, hemangioma/vascular malformation, tumor apoplexy, tumor invasion of blood vessels, or active gastrointestinal ulcer, esophageal varices, or central nervous system (CNS) metastases with intracranial lesions that have potential bleeding risk, as determined by the investigator to have a significant risk of hemorrhage.
• History of severe skin diseases requiring systemic therapy within the past 2 years, such as eczema, atopic dermatitis, burns, seborrheic dermatitis, psoriasis, severe acne, etc.
• Patients with history of hypersensitivity or anaphylactic reactions (including immediate severe hypersensitivity reactions) of CTCAE v6.0 Grade > 3 following prior use of any drug or biologic product.
• Requirement for anticoagulant or antiplatelet therapy that cannot be interrupted prior to intratumoral injection, including: aspirin that cannot be discontinued within 7 days prior to injection; coumarins that cannot be discontinued within 7 days prior to injection; direct thrombin inhibitors (dabigatran) or direct Factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) that cannot be discontinued within 4 days prior to injection; low-molecular-weight heparin (LMWH) that cannot be discontinued within 24 hours prior to injection; and unfractionated heparin (UFH) that cannot be discontinued for more than 4 hours prior to injection.
• Use of immunomodulatory agents within 14 days prior to the first dose of the investigational product, including but not limited to thymosin, IL-2, IFN, etc.
• Presence of other conditions requiring systemic anti-infective treatment within 4 weeks prior to the first dose of the investigational product, or active local infection at the target lesion intended for injection within 4 weeks prior to the first dose, including but not limited to hospitalization due to infectious complications, bacteremia, severe pneumonia, or active tuberculosis.
• Receipt of other investigational drugs or therapies not yet approved for marketing within 4 weeks prior to the first dose of the investigational product, or receipt of live or live-attenuated vaccines within 4 weeks prior to the first dose.
• Study participants who had undergone major surgery requiring hospitalization within 4 weeks before the first use of the investigational drug, or who were expected to undergo major surgery during the trial.
• Inability to discontinue concomitant use of sensitive substrate drugs with a narrow therapeutic index that are metabolized by CYP450 enzymes within 5 half-lives prior to the first dose of the investigational product.
• Any known mental illness or substance abuse that may interfere with the participant's ability to cooperate with the trial.
• According to the evaluation of the investigators, the treatment risks are high, including but not limited to the high risk of bleeding, possible damage to the surrounding important tissue structures, the risk of shock caused by dizzy with blood and needles, and the risk of aggravating local infection.
• If study participants plan to participate in another clinical trial during the trial period, plan to leave the trial site, or otherwise are not suitable for participation in the trial as assessed by the investigator.