XNW27011 Study of Advanced Solid Tumor Subjects Who Failed Standard Therapies.

Inclusion Criteria:

• Phase I (Dose Escalation)：

1. Patients are willing and able to provide written informed consent or whereconsent is provided by legally authorized representatives.

2. Age ≥18 years old when signing the informed consent form.

3. Patients with a histologically or cytologically-confirmed, locally advanced ormetastatic solid tumor, which has failed on standard therapy or is intolerableto available standard therapy, or there is no available standard therapy forthe tumor. The advanced solid tumors include but are not limited to gastric andgastroesophageal junction adenocarcinoma, pancreatic adenocarcinoma, esophagealadenocarcinoma, ovarian cancer, lung cancer, colorectal cancer, andbiliarytract cancer.

4. The enrollment is not restricted to patients with tumor expressing CLDN18.2.However patients are required to provide tumor tissue sections for CLDN18.2expression confirmation.

5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

6. Estimated life expectancy > 12 weeks.

7. At least one measurable cancer lesion as defined by the Response EvaluationCriteria in Solid Tumors (RECIST version 1.1).

8. Adequate organ function, evidenced by the following laboratory results:

9. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.

10. Platelet count ≥ 100 × 109/L.

11. Hemoglobin ≥ 9.0 g/dL.

12. Total bilirubin ≤ 1.5 × the upper limit of normal (ULN).

13. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 × ULN (if liver metastases are present, ≤ 3 × ULN).

14. Creatinine clearance (Ccr) ≥60 mL/minute as calculated using themodifiedCockcroft-Gault equation.

15. QTc prolongation to ≤480 milliseconds (ms) (based on the average of 3screening electrocardiograms) (QTc interval corrected by Fridericia'sCorrection Formula, QTcF = QT/(RR0.33).

16. Echocardiographic LVEF (left ventricular ejection fraction) ≥ 50%.

17. Female patients of childbearing potential, who are willing to use a highlyeffective method of birth control during the study, and for at least 180 daysafter the last dose of study medication.

18. Childbearing potential is defined as any female who has experiencedmenarche and does not meet the criteria for postmenopausal, which isdefined as the past 12 months with no menses without an alternativemedical cause or permanently sterilized (e.g., has undergone bilateraltubal occlusion/ligation, hysterectomy, bilateral oophorectomy, bilateralsalpingectomy).

19. A highly effective method of birth control is defined as one that resultsin a low failure rate (i.e., <1% per year) when used consistently andcorrectly, such as implants, injectables, combined oral contraceptives,intrauterine devices, sexual abstinence, or a vasectomized partner.

20. Male patients with female sexual partners of childbearing potential areeligible for inclusion if they agree to use medically acceptable birth controlduring the study, and for 180 days after the last dose of study medication.Sexual abstinence, vasectomy, or a condom used with a spermicide are medicallyacceptable birth control methods for males. Male subjects must agree not todonate sperm for a period of 180 days after the last dose of study treatment.

PHASE Ⅱ (DOSE EXTENSION)：

1. Subjects are willing and able to provide written informed consent or where consentis provided by legally authorized representatives.

2. Age ≥18 years old when signing the informed consent form.

3. Patients with histologically or cytologically confirmed, locally advanced ormetastatic solid tumors, which have failed on standard therapy, or are intolerableto available standard therapy, or for which there is no available standard therapy. Patients are grouped by anatomic locations of solid tumors: Group A: gastric adenocarcinoma/gastroesophageal junction adenocarcinoma. Group B:pancreatic adenocarcinoma. Group C: ovarian cancer. Group D: other cancer includingesophagus adenocarcinomas, lung cancer, colorectal cancer, and biliary tract cancer.

4. Only patients with tumor expressing CLDN 18.2 will be enrolled. The most recentlyavailable tumor samples of patients will be examined by IHC at a central laboratory.If no archived tumor samples are available or the archived tumor samples are deemedto be inappropriate for the confirmation of CLDN18.2 expression, a new biopsy mustbe performed to obtain the tumor sample to confirmation of CLDN18.2 expression.

5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

6. Estimated life expectancy > 12 weeks.

7. At least one measurable cancer lesion as defined by the Response Evaluation Criteriain Solid Tumors (RECIST version 1.1).

8. Adequate organ function, evidenced by the following laboratory results:

9. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.

10. Platelet count ≥ 100 × 109/L.

11. Hemoglobin ≥ 9.0 g/dL.

12. Total bilirubin ≤ 1.5 × the upper limit of normal (ULN).

13. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5× ULN (if liver metastases are present, ≤ 3 × ULN).

14. Creatinine clearance (Ccr) ≥50 mL/minute as calculated using the modifiedCockcroft-Gault equation.

15. QTc prolongation to ≤ 480 millisecond (ms) (based on the average of 3 screeningelectrocardiograms) (QTc interval corrected by Fridericia's Correction Formula,QTcF = QT/(RR0.33).

16. Echocardiographic LVEF (left ventricular ejection fraction) ≥ 50%.

17. Female patients of childbearing potential, who are willing to use a highly effectivemethod of birth control during the study and for at least 180 days following thelast dose of study medication.

18. Childbearing potential is defined as any female who has experienced menarcheand does not meet the criteria for postmenopausal, which is defined as the past 12 months with no menses without an alternative medical cause or permanentlysterilized (e.g., has undergone bilateral tubal occlusion/ligation,hysterectomy, bilateral oophorectomy, bilateral salpingectomy).

19. A highly effective method of birth control is defined as one that results in alow failure rate (i.e., <1% per year) when used consistently and correctly,such as implants, injectables, combined oral contraceptives, intrauterinedevices, sexual abstinence, or a vasectomized partner.

20. Male patients with female sexual partners of childbearing potential are eligible forinclusion if they agree to use medically acceptable birth control for 180 daysfollowing the last dose of study medication. Sexual abstinence, vasectomy, or acondom used with a spermicide are medically acceptable birth control methods formales. Male subjects must agree not to donate sperm for a period of 180 days afterthe last dose of study treatment.

Exclusion Criteria:

• PHASE I (DOSE ESCALATION)：

1. Prior severe allergic reaction or intolerance to a monoclonal antibody,including humanized or chimeric antibodies.

2. Prior severe allergic reaction or intolerance to the Topoisomerase I Inhibitoror Topoisomerase Inhibitor-Based ADC (e.g: Fam-trastuzumab deruxtecan-nxki,Sacituzumab govitecan-hziy, Irinotecan, Topotecan) or any excipient in theXNW27011 formulation.

3. Having any of the following medical conditions in the past or at present:

4. Acquired or congenital immunodeficiency diseases or organ transplantation.

5. Past myocardial infarction (within 6 months before the firstadministration), hospitalization for congestive heart failure within 12months before the first administration, severe or unstable angina,coronary or peripheral artery bypass grafting, New York Heart Association (NYHA) grade Ⅲ or IV heart failure, uncontrollable hypertension (SystolicBP ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg at rest).

6. Concomitant diseases that will seriously endanger the safety of thesubject or affect the completion of the tests, such as activegastrointestinal bleeding, active peptic ulcer, intestinal obstruction,intestinal paralysis, interstitial pneumonia, lung fibrosis, kidneyfailure, and uncontrolled diabetes(HbA1c>8%).

7. History of or currently suffering from uncontrolled primary ormetastasized brain tumors, except that the investigator believes that thedisease has been stabilized in patients, or whose local treatment hasended.

8. History of significant cerebrovascular disease/event, including stroke orintracranial hemorrhage, within 6 months before the first dose of theXNW27011.

9. Past or current mental illness that is difficult to control.

10. Human immunodeficiency virus (HIV) infection, syphilis infection, oractive hepatitis B or C infection. Note: Syphilis infection refers toactive syphilis or latent syphilis that requires treatment.

11. Patients who have active infections that required systemic treatmentwithin 2 weeks prior to the first dose of XNW27011.

12. Clinically significant third spacing (large amount of pleural fluid orascites, judged by treating physician) that is uncontrollable by drainageor other methods.

13. Having any adverse event from prior anti-tumor treatments that have notyet recovered to Grade 0 or 1 per NCI-CTCAE v5.0 (except alopecia).

14. History of treatment:

15. Patients who have previously participated in clinical trials of otherdrugs within 4 weeks before the first dose of XNW27011.

16. Received anti-tumor therapy (chemotherapy, radiotherapy, immunologictherapy or biological therapy,) within 3 weeks, prior to the first dose ofXNW27011, or received small molecular targeted therapy, anti-tumormedicinal herb or proprietary Chinese traditional medicines within 2weeks, or received palliative radiotherapy for bone metastases within 2weeks, or received nitrosoureas or mitomycin C within 6 weeks.

17. Received major surgical or interventional treatment within 4 weeks priorto the first dose of XNW27011, with the exception of tumor biopsy,puncture, etc.

18. Received systemic steroid therapy for a long period of time (≥20 mg ofprednisone/day or equivalent for >7 days). (Short-term use of no more than 7 days or steroid therapy withdrawal longer than 2 weeks prior to thefirst dose of XNW27011 can be selected).

19. Received live vaccines within 4 weeks prior to the first dose of XNW27011or plan to take any live vaccine during the study period.

20. Received strong inhibitors or inducers of CYP3A4, or strong inhibitors ofCYP2D6 within 2 weeks or five half-lives (whichever is shorter) of theinhibitor or inducer prior to the first dose of XNW27011.

21. Women who are pregnant or breastfeeding, or women whose serum pregnancy testresults are positive during the screening period (female patients who areinfertile do not need to undergo a pregnancy test, e.g., female patients whounderwent hysterectomy, bilateral tubal occlusion/ ligation, bilateralsalpingectomy, or bilateral oophorectomy in the past, or women with resectionor amenorrhea ≥12 months).

22. Patients who have poor compliance and are not expected to cooperate to completethe study procedures, or who are deemed unsuitable to participate in theclinical research by the investigator. PHASE Ⅱ (DOSE EXTENSION)：

23. Prior severe allergic reaction or intolerance to a monoclonal antibody,including humanized or chimeric antibodies.

24. Prior severe allergic reaction or intolerance to the Topoisomerase I Inhibitoror Topoisomerase Inhibitor-Based ADC (e.g: Fam-trastuzumab deruxtecan-nxki,Sacituzumab govitecan-hziy, Irinotecan, Topotecan) or any excipient in theXNW27011 formulation.

25. Having any of the following medical conditions in the past or present:

26. Acquired or congenital immunodeficiency diseases or organ transplantation.

27. Past myocardial infarction (within 6 months before the firstadministration), hospitalization for congestive heart failure within 12months before the first administration, severe or unstable angina,coronary or peripheral artery bypass grafting, New York Heart Association (NYHA) grade Ⅲ or IV heart failure, uncontrollable hypertension (SystolicBP ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg at rest).

28. Concomitant diseases that will seriously endanger the safety of thesubject or affect the completion of the study, such as activegastrointestinal bleeding, active peptic ulcer, intestinal obstruction,intestinal paralysis, interstitial pneumonia, lung fibrosis, kidneyfailure, and uncontrolled diabetes (HbA1c>8%).

29. Previously or currently suffering from uncontrollable primary ormetastasized brain tumors, except that the investigator believes that thedisease has been stabilized in patients, or whose local treatment hasended.

30. History of significant cerebrovascular disease/event, including stroke orintracranial hemorrhage, within 6 months before the first dose ofXNW27011.

31. Past or current mental illness that is difficult to control.

32. Human immunodeficiency virus (HIV) infection, syphilis infection, oractive hepatitis B or C infection. Note: Syphilis infection refers to active syphilis or latent syphilis thatrequires treatment.

33. Patients who have active infections that required systemic treatmentwithin 2 weeks prior to the first dose of XNW27011.

34. Has multiple primary malignancies within 5 years, except adequatelyresected non-melanoma skin cancer, curatively treated in-situ disease, andother solid tumors curatively treated.

35. Clinically significant third spacing (large amount of pleural fluid orascites, judged by treating physician) that is uncontrollable by drainageor other methods.

36. Having any adverse event from prior anti-tumor treatments that have notyet recovered to Grade 0 or 1 per NCI-CTCAE v5.0 (except alopecia).

37. History of treatment:

38. Patients who have previously been treated with ADCs or CAR-T targetingCLDN18.2, or participated in clinical trials of other drugs within 4 weeksbefore the first dose of XNW27011.

39. Received anti-tumor therapy (chemotherapy, radiotherapy, immunologictherapyor biological therapy) within 3 weeks, prior to the first dose ofXNW27011, or received small molecular targeted therapy, anti-tumormedicinal herb or proprietary Chinese traditional medicines within 2weeks, or received palliative radiotherapy for bone metastases within 2weeks, or received nitrosoureas or mitomycin C within 6 weeks.

40. Have received major surgical or interventional treatment within 4 weeksprior to the first dose of XNW27011, with the exception for tumor biopsy,puncture, etc.

41. Received systemic steroid therapy for a long period of time (≥20 mg ofprednisone/day or equivalent for >7 days). (Short-term use of no more than 7 days or steroid therapy withdrawal longer than 2 weeks prior to thefirst dose of XNW27011 can be selected).

42. Received live vaccines within 4 weeks prior to the first dose ofXNW27011or planned to take any live vaccine during the study period.

43. Received strong inhibitors or inducers of CYP3A4, or strong inhibitors ofCYP2D6 within 2 weeks or five half-lives (whichever is shorter) of theinhibitor or inducer prior to the first dose of XNW27011.

44. Women who are pregnant or breastfeeding, or women whose serum pregnancy testresults are positive during the screening period (female patients who areinfertile do not need to undergo a pregnancy test, e.g., female patients whounderwent hysterectomy, bilateral tubal occlusion/ligation, bilateralsalpingectomy, or bilateral oophorectomy in the past and women with resectionor amenorrhea ≥12 months).

45. Patients who have poor compliance and are not expected to cooperate to completethe study procedures, or who are deemed unsuitable to participate in theclinical research by the investigator.