A Study of RC148 As a Single Agent and Combination Therapy in Patients with Locally Advanced Unresectable or Metastatic Malignant Solid Tumors

Inclusion Criteria:

1. Be able to participate in the study voluntarily and willing to provide writteninformed consent.

2. male or female ≥18 years (phase Ⅰ), 18 to 75 years old (Including 18 and 75 years,phase Ⅱ).

3. Must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

4. Projected life expectancy of at least 12 weeks.

5. At least one measurable target lesion based on imaging according to RECIST v1.1criteria (For patients who have received prior radiotherapy, radiotherapy-treatedlesions may be considered as target lesions if the lesion is measurable according toRECIST v1.1 criteria and there is evidence of significant progression afterradiotherapy.);

6. Requirements for inclusion of subjects at different stages: Phase I (RC148 monotherapy): Patients with locally advanced unresectable ormetastatic malignant solid tumors whose disease has progressed with standardtherapy, or who are unable to tolerate standard therapy, or in whom the subjectrefuses standard therapy; Phase II (Combination Therapies): Cohort 1 (non-small cell lung cancer): Patients with locally advanced unresectableor metastatic malignant solid tumors with disease progression on standard therapy,or intolerance of standard therapy, or refusal of standard therapy. Cohort 2 (HER2-expressing cervical cancer): Subjects with advanced non-small celllung cancer diagnosed by histological or cytological examination, locally advancedor metastatic, with AGA- confirmed by prior genetic testing, who have received aPD-1/PD-L1 inhibitor and platinum-based chemotherapy as a first or second-lineadvanced treatment, and who have not received docetaxel chemotherapy. Cohort 3 (HER2 expressing gastric cancer): Histologically and/or cytologicallyconfirmed locally advanced or metastatic gastric adenocarcinoma (includinggastroesophageal junction adenocarcinoma) with HER2 expression (IHC ≥1+). Subjectswho have progressed or are intolerant to standard first-line therapy only (PD-1/PD-L1 inhibitor + platinum-containing chemotherapy ± trastuzumab, and notincluding paclitaxel). Disease progression during neoadjuvant therapy and within 6months of the end of adjuvant therapy will also be considered a failure offirst-line therapy. Cohort 4 (MSLN-expressing lung adenocarcinoma): Histologically or cytologicallyconfirmed lung adenocarcinoma without other pathologic components; driver genenegative, MSLN-expressing (IHC ≥1+) advanced lung adenocarcinoma subjects who havereceived PD-1/PD-L1 inhibitor and platinum-based chemotherapy (combination orsequential) and have not received paclitaxel-based chemotherapy. Cohort 5 (platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer):pathologic type needs to be high-grade serous ovarian cancer; Subjects who haveprogressed on prior 1-4 lines of antitumor therapies; Definition ofplatinum-resistance: 1) Patients who have received 1 line of platinum-based therapymust have received at least 4 cycles of platinum, must have had a response (CR orPR), and then progressed between >3 months and ≤6 months after the date of the lastplatinum; 2) Patients who have received 2 or 3 lines of platinum-based therapiesmust have received at least 4 cycles of platinum and have progressed on or within 6months after the last dose of platinum. Cohort 6 (platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer):Pathological type needs to be high-grade serous EOC; Subjects who have received 1-4lines of prior antitumor therapies were included. Cohort 7 (MSLN-expressing cervical cancer): Subjects with recurrent or metastaticcervical cancer expressing mesothelin (MSLN) (IHC ≥1+) that is histologicallyconfirmed, ineligible for surgery or radiotherapy, and has progressed after at least 1L of platinum-based chemotherapy.

7. Participants agree to provide pre-treatment archived/biopsied tumor samples forbiomarker-related testing such as retrospective programmed cell death protein 1 (PD-L1) expression levels. Biopsies will be considered at screening only if archivedsamples are not available. Fresh tumor biopsies will not be considered ifsignificant risk procedures are required per the discretion of the Investigator.

8. Adequate bone marrow, liver, and renal function defined as: No platelet or red blood cell transfusion within 14 days prior to performing routineblood tests, no correction with thrombopoietin (TPO), erythropoietin (EPO),granulocyte colony-stimulating factor (G-CSF), or interleukin-11 (IL-11), absoluteneutrophil count (ANC) ≥ 1.5 × 10^9/L, platelets ≥ 100 × 10^9/L, and Hemoglobin ≥ 90g/L. Serum total bilirubin ≤1.5 × upper limit of normal (ULN), ALT, AST ≤2.5 × ULN (≤5 ×ULN in case of known liver metastases), albumin ≥30 g/L International NormalizedRatio (INR) ≤1.5×ULN, Activated Partial Thromboplastin Time (APTT) ≤1.5×ULN. Serum creatinine ≤ 1.5 x ULN. Urinalysis results for urinary protein <++.

9. For subjects in Cohort 1 (Non-Small Cell Lung Cancer) and Cohort 4 (LungAdenocarcinoma) of the Phase II Combined Protocol, pulse oximetry (O2 saturation)measured under unoxygenated conditions was required to be >92%.

10. Cardiac function: left ventricular ejection fraction ≥50%.

11. Male or female subjects with fertility must agree to take effective contraceptivemeasures during the study period and within 6 months after the end of the lastmedication, such as double-barrier contraceptive methods, condoms, oral orinjectable contraceptives, intrauterine contraceptive device.

Exclusion Criteria:

1. Pregnant or lactating.

2. Cohort 1 in Phase II, patients with histologically or cytologically confirmednon-small cell lung cancer, other than squamous lung cancer and lung adenocarcinoma, (including subjects with squamous or adenocarcinoma in combination with otherpathologic types of non-small cell lung cancer;) prior treatment with docetaxel, oran antitumor agent that targets VEGF/VEGFR; and treatment with at least 2 cycles ofan immune checkpoint inhibitor, with a best response of PD, or best response ofCR/PR/SD with disease progression within 6 months of first dose.

3. Cohorts 4-7 in Phase II, patients with ocular corneal conditions at screening suchas congenital corneal dystrophy, meibomian gland dysfunction (MGD), viral keratitis (dendritic, map-like, corneal stromal keratitis), uveitis, corneal endothelialdecompensation, glaucoma, iridocorneal endothelial syndrome (ICE).

4. Subjects with active hepatitis B or C; human immunodeficiency virus (HIV)-positivesubjects.

5. Those who have received a live vaccine within 28 days prior to the first RC148administration or who plan to receive any live vaccine during the study period.

6. Participant with a history of other acquired/congenital immunodeficiency diseases ororgan transplantation.

7. Active autoimmune disease requiring systemic therapy, such as systemic lupuserythematosus, psoriasis requiring systemic therapy, or rheumatoid arthritis, withinthe past 2 years; however, alternative therapies are not considered systemictherapies and are permitted for use and enrollment.

8. Subject has received an immune checkpoint inhibitor (anti-PD-1/PD-L1/CTLA-4antibody) or other immune checkpoint inhibitor therapy within 28 days prior toinitiation of treatment with the study drug or has experienced permanentdiscontinuation of immunotherapy due to toxicity of immune checkpoint inhibitortherapy prior to receiving administration of the study drug.

9. Subjects who have participated in a clinical trial of another drug and received thetest drug within 4 weeks prior to the first dose of RC148.

10. Prior concomitant treatment with antitumor agents targeting VEGF/VEGFR andPD-1/PD-L1 (except for subjects with cervical cancer). For cohorts 2-3 in Part 2,subjects with prior antibody-drug conjugates treatment. For cohorts 4-7 in Part 2,subjects with prior antibody-drug conjugates and MSLN-targeting drugs.

11. Known hypersensitivity or delayed hypersensitivity to certain components of thestudy drug or to similar drugs.

12. Participant who are under the treatment of anticoagulant drugs. Participants usingprophylactic doses of heparin are eligible in the study.

13. Subject received last systemic antitumor therapy, including surgery, chemotherapy,radiotherapy, and biologic therapy within 4 weeks prior to the first study drugadministration; received small molecule tyrosine kinase inhibitor therapy orimmunotherapy within 2 weeks prior to the first drug administration; or receivedherbal therapy for antitumor indications within 1 week prior to the first drugadministration or received bone/other solitary metastases within 2 weeks prior tothe first study drug administration Palliative radiotherapy.

14. Previous adverse reactions resulting from previous anti-tumour therapies, which havenot returned to Grade 1 according to NCI-CTCAE v5.0 at screening.

15. Presence of grade ≥2 sensory or motor neuropathy.

16. Presence of third interstitial fluid with clinical symptoms or requiringintervention.

17. Active infection of clinical significance judged by the investigator.

18. Active gastrointestinal bleeding, history of hemoptysis, peptic ulcer, or ahemorrhagic event with NCI CTCAE (V5.0) ≥ grade 2 within 4 weeks prior to screening;or the presence of severe esophagogastric varices, nosebleeds; and in the case ofsubjects with gastric cancer, a tumor lesion with a tendency to bleed.

19. Presence of systemic diseases that, in the judgment of the investigator, are notunder stable control, including diabetes mellitus, hypertension, cirrhosis of theliver, etc.

20. Those with previous and current clinical manifestations or high risk factors forinterstitial lung disease (ILD), drug-associated pneumonia, radiation pneumonitis,severely impaired lung function, or suspected interstitial lung disease.

21. Clinically relevant pyelonephrosis that cannot be reduced by ureteral stenting orpercutaneous drainage.

22. History of gastrointestinal perforation and/or fistula, gastrointestinalobstruction, inflammatory bowel disease, or bowel resection within the past 6months.

23. Screening QTc interval >450 ms (males), QTc interval >470 ms (females); previousfamily or personal history of long/short QT interval syndrome; history ofventricular arrhythmia considered clinically significant by the investigator orcurrently receiving antiarrhythmic medications or implantation of an arrhythmiadefibrillation device.

24. Experienced an arterial/venous thromboembolic event such as cerebrovascularaccident, deep vein thrombosis, pulmonary embolism, cerebral infarction, orexperienced a history of hypertensive crisis or hypertensive encephalopathy within 6months prior to initiation of study treatment.

25. History of myocardial infarction, severe or unstable angina pectoris, coronary orperipheral artery bypass graft or vascular disease, New York Heart Association (NYHA) grade ≥3 heart failure within 6 months prior to screening; history offulminant, acute, chronic relapsing, or persistent myocarditis, pericarditis, orepicarditis from any cause within 1 year prior to screening.

26. Subjects on systemic therapy with corticosteroids (daily prednisone ≥10 mg/day orequivalent dose of drug) or other immunosuppressive medications within 2 weeks offirst study administration.

27. Subjects with the presence of brain metastases who have been previously treated forbrain metastases may be considered for enrollment (exclusion of brain metastasesfrom gastric cancer): provided that the disease is stable, no disease progressionhas occurred as determined by imaging within 4 weeks prior to dosing, and allneurological symptoms have returned to baseline levels, and that the use ofradiation, surgical, or steroid therapy has been discontinued for at least 28 daysprior to the first dose of the drug; in the case of carcinomatous meningealmetastases, regardless of their clinical stabilization of symptoms, should beexcluded.

28. Major surgery or intervention with incomplete recovery (except tumor biopsy orpuncture) within 4 weeks prior to the first dose of study drug; or gross needleaspiration biopsy or other minor surgery, excluding placement of vascular infusiondevices, within 7 days prior to initiation of study drug therapy.

29. Screening imaging showing tumor invasion of large blood vessels or imaging evidenceof tumor invasion of vital organs or risk of developing a fistula; or imagingevidence of tumor encircling a large blood vessel or entry into the study causing arisk of hemorrhage.

30. Other malignancies were present within 5 years before the initiation of studyadministration, except for malignancies that would be expected to be cured withtreatment.

31. Previous or current uncontrollable mental illness.

32. Subjects with poor compliance who were not expected to cooperate in completing trialprocedures.

33. Any other disease, metabolic abnormality, physical examination abnormality, orlaboratory test abnormality that, in the judgment of the Investigator, gives reasonto suspect that the subject has a disease or condition that makes the subjectunsuitable for the use of the investigational drug, or that would interfere with theinterpretation of the results of the study, or that would place the subject at highrisk.