YSCH-01 Via Nebulization in Pulmonary Metastasis of Advanced Solid Tumors and Non-small Cell Lung Cancer (NSCLC)

An Open-label, Single-center Study to Evaluate the Dose Escalation and Cohort Expansion of YSCH-01 in Subjects With Pulmonary Metastasis of Advanced Solid Tumors and Advanced Non-small Cell Lung Cancer by Nebulized Inhalation Administration

This is an open-label, dose-escalation and cohort expansion study to evaluate the safety and preliminary efficacy of YSCH-01 in subjects with pulmonary metastasis of advanced solid tumors and advanced non-small cell lung cancer by nebulized inhalation administration. This study is consisting of two phases: the dose escalation phase and the cohort expansion phase.

In dose escalation phase, subjects with pulmonary metastasis of advanced solid tumors and advanced non-small cell lung cancer will be enrolled to receive YSCH-01 treatment by inhalation via nebulization. The "3+3" design will be adopted to explore the MTD and determine RP2D. Two dose groups will be established as follows:

Dose group 1: 2E+11 VP; Dose group 2: 4E+11 VP. All the subjects received a single dose of YSCH-01 treatment, followed by a 21-day DLT observation period. If no DLT occurred, the YSCH-01 will administered once a week thereafter until the investigator deemed that the subjects no longer benefited significantly, experienced intolerable toxicity, withdrew their informed consent, had disease progression, died, were lost to follow-up, or the investigator deemed that terminating the treatment was in the best interest of the subjects (whichever occurred first).

In cohort expansion phase, subjects will receive the optimal dose and administration schedule determined during the dose escalation phase. The cohort expansion phase further evaluated the safety and preliminary efficacy of YSCH-01 and planned to include 3 cohorts, with 10-30 subjects in each cohort.

Inclusion Criteria:

1. Subjects are able to understand and comply with protocol requirements, in the investigator's judgment.

2. Subjects are willing to sign the informed consent form (ICF) before any study procedures are initiated.

3. Male or female patients aged ≥18 years old and ≤75 years old.

4. Dose escalation phase: Subjects with histologically or cytologically confirmed advanced unresectable/relapsed metastatic non-small cell lung cancer (NSCLC) or advanced solid tumors with lung metastases who have failed prior standard therapy, have no standard therapy or are not eligible for standard therapy.

   Cohort expansion phase:

   • Cohort 1: Subjects with advanced unresectable or metastatic NSCLC who have failed prior immunotherapy and/or platinum-based chemotherapy, including:
   • Those with driver gene mutations positive for which no targeted therapy is approved;
   • Those without driver gene mutations.
   • Cohort 2: Subjects with histologically or cytologically confirmed relapsed sarcoma with lung metastases after surgical resection (lung metastases only).
   • Cohort 3: Subjects with histologically or cytologically confirmed relapsed hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), or other sensitive tumors with lung metastases after surgical resection (lung metastases only).

5. Subjects with relapsed, refractory, or locally advanced lesions are eligible; subjects with curable or resectable lesions are not eligible.

6. Subjects must have at least one measurable lesion as defined by RECIST 1.1, i.e., non-lymph node lesions with a long diameter ≥10 mm or a lymph node lesion with a short diameter ≥15 mm on cross-sectional imaging (CT or MRI).

7. Pulmonary function test: FEV1/expected FEV1 ≥50% and FVC ≥50% of expected value.

8. Subjects have adequate hematologic, hepatic, renal, and coagulation function.

9. Eligible subjects of childbearing potential (male and female) must agree to use reliable contraceptive methods during the study and for at least six months after the last dose.

10. Women of childbearing potential must have a negative pregnancy test within 7 days before starting treatment.

11. Subjects with an eastern cooperative oncology group (ECOG) score of 0-1 and an expected survival of at least 12 weeks.

12. All adverse events (AEs) from prior treatment or surgery must have recovered to Grade 1 or baseline.

Exclusion Criteria:

1. The subject has received chemotherapy or antibody therapy, molecular targeted therapy, hormone therapy, therapeutic or palliative radiotherapy within 21 days before the first dose, has received anti-tumor traditional Chinese medicine therapy within 1 week before the first dose, or has received immune checkpoint inhibitors (e.g., PD-1, PD-L1 monoclonal antibodies) within 42 days.

2. The subject has experienced cardiac-related adverse reactions, or ≥Grade 3 immune-related adverse events (irAEs) or severe irAEs (excluding skin or endocrine irAEs that have recovered to Grade 1 or normal after treatment), or >Grade 2 cytokine release syndrome (CRS) from prior anti-tumor therapy.

3. The subject has systemic diseases that are not stably controlled after treatment, such as diabetes, severe organic cardiovascular or cerebrovascular diseases, hypertension, second-degree or higher atrioventricular block, myocardial infarction within the past 6 months, or cerebral infarction within the past 6 months.

4. The subject has uncontrolled infectious diseases, active hepatitis B (positive for anti-hepatitis B core (HBc) antibody and hepatitis B virus (HBV)-DNA > the lower limit of detection(LLOD) of the study center); active hepatitis C (positive for anti-hepatitis C virus (HCV) antibody and HCV RNA > LLOD); or positive for anti-human immunodeficiency virus (HIV)-1 or HIV-2 antibodies.

5. The subject has uncontrolled active infection of ≥Grade 3 with significant clinical relevance according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0.

6. The subject has had other malignancies within the past 5 years, excluding basal cell or squamous cell carcinoma of the skin that has been cured by radical resection, or carcinoma in situ of the cervix.

7. The subject has lesions located in high-risk positions (including those near the airways, major blood vessels, etc.) that may cause occlusion or compression due to tumor enlargement, or erosion into major vessels due to necrosis, or encasement of major vascular structures (e.g., pulmonary artery), or tumors adjacent to important neurovascular structures.

8. Known symptomatic, untreated, or active central nervous system (CNS) metastases. Subjects with asymptomatic and previously treated brain metastases may participate provided that:

   • Imaging is stable, i.e., no evidence of disease progression on imaging during the screening period (note: imaging should be performed after local therapy for CNS);
   • Clinically stable with no history of intracranial hemorrhage or spinal cord hemorrhage;
   • Does not require steroid therapy for at least 14 days before the first dose of study treatment;
   • Has not received stereotactic radiotherapy within 7 days before the first dose, whole-brain radiotherapy within 14 days before the first dose, or neurosurgery within 28 days before the first dose;
   • Metastases are limited to the cerebellum or supratentorial region (i.e., no metastases to the midbrain, pons, medulla oblongata, or spinal cord);
   • Must have measurable disease outside the CNS.

9. History of leptomeningeal disease.

10. The subject has active autoimmune disease or a history of autoimmune disease with potential for recurrence, such as ulcerative colitis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, autoimmune vasculitis, or granulomatosis with polyangiitis (Wegener's granulomatosis). Subjects with the following conditions are permitted: autoimmune hypothyroidism requiring only hormone replacement therapy; skin diseases not requiring systemic treatment (e.g., eczema involving <10% of body surface area).

11. The subject has a known allergy to any component of the study drug or immunotherapy.

12. The subject has a past or current history of organ dysfunction.

13. The subject requires systemic corticosteroids (equivalent to >10 mg prednisone/day) within 14 days before enrollment or during the study period. Subjects are eligible for cohort enrollment in the following cases: topical (excluding inhaled) corticosteroid use, or short-term (≤7 days) use of glucocorticoids to prevent or treat non-autoimmune allergic conditions.

14. History of pulmonary fibrosis, or current interstitial pneumonia, pneumoconiosis, chemical pneumonia, or other severe pulmonary function impairment, or conditions that make nebulized administration difficult due to prior medical history, such as asthma, airway obstruction, etc.

15. Current presence of uncontrolled pleural effusion, pericardial effusion, or ascites.

16. The subject lacks legal capacity or has limited legal capacity and is unable to complete informed consent.

17. The subject has participated in another clinical trial of a drug or medical device within the previous 4 weeks or 5 half-lives, whichever is shorter.

18. The subject has severe and uncontrolled disease or other conditions that may affect their participation in this study, as determined by the investigator.

19. The subject is pregnant or breastfeeding.

20. The subject receives any live vaccine during the screening period or treatment period.