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

This is a global, multi-center, open-label, Phase I/II first-in-human study of XNW27011 monotherapy as an investigational product (IP) in patients with locally advanced and/or metastatic solid tumors who have failed or are intolerant to standard therapies. XNW27011 is an antibody-drug conjugate (ADC) targeting Claudin 18.2 (CLDN18.2), a transmembrane protein important to tight junctions. The study consists of 2 parts: Part 1 is the dose-escalation phase (Phase I), and Part 2 is the does-expansion phase (Phase II). In phase I part of the study, approximately 42 patients with locally advanced and/or metastatic solid tumors will be enrolled, irrespective of CLDN18.2 expression. However, the most recently available tumor tissue specimen will be collected (if available) for a retrospective CLDN18.2 expression confirmation. In phase II part of the study, only patients with confirmed CLDN18.2 expression by IHC in the central laboratory will be enrolled.The phase II part of the study will consist of the following four groups，Up to three dose cohorts for each patient group are planned currently. Each dose cohort will include approximately 20 patients. Approximately 240 patients evaluable will be enrolled in Phase Ⅱ part of the study.

Inclusion criteria

• Phase I (Dose Escalation)：

• Patients are willing and able to provide written informed consent or where consent is provided by legally authorized representatives.
• Age ≥18 years old when signing the informed consent form.
• Patients with a histologically or cytologically-confirmed, locally advanced or metastatic solid tumor, which has failed on standard therapy or is intolerable to available standard therapy, or there is no available standard therapy for the tumor. The advanced solid tumors include but are not limited to gastric and gastroesophageal junction adenocarcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, lung cancer, colorectal cancer, andbiliary tract cancer.
• The enrollment is not restricted to patients with tumor expressing CLDN18.2. However patients are required to provide tumor tissue sections for CLDN18.2 expression confirmation.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Estimated life expectancy > 12 weeks.
• At least one measurable cancer lesion as defined by the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).
• Adequate organ function, evidenced by the following laboratory results:

• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.
• Platelet count ≥ 100 × 109/L.
• Hemoglobin ≥ 9.0 g/dL.
• Total bilirubin ≤ 1.5 × the upper limit of normal (ULN).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 × ULN (if liver metastases are present, ≤ 3 × ULN).
• Creatinine clearance (Ccr) ≥60 mL/minute as calculated using themodified Cockcroft-Gault equation.
• QTc prolongation to ≤480 milliseconds (ms) (based on the average of 3 screening electrocardiograms) (QTc interval corrected by Fridericia's Correction Formula, QTcF = QT/(RR0.33).
• Echocardiographic LVEF (left ventricular ejection fraction) ≥ 50%.
• Female patients of childbearing potential, who are willing to use a highly effective method of birth control during the study, and for at least 180 days after the last dose of study medication.

• Childbearing potential is defined as any female who has experienced menarche and does not meet the criteria for postmenopausal, which is defined as the past 12 months with no menses without an alternative medical cause or permanently sterilized (e.g., has undergone bilateral tubal occlusion/ligation, hysterectomy, bilateral oophorectomy, bilateral salpingectomy).
• A highly effective method of birth control is defined as one that results in a low failure rate (i.e., <1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or a vasectomized partner.
• Male patients with female sexual partners of childbearing potential are eligible for inclusion if they agree to use medically acceptable birth control during the study, and for 180 days after the last dose of study medication. Sexual abstinence, vasectomy, or a condom used with a spermicide are medically acceptable birth control methods for males. Male subjects must agree not to donate sperm for a period of 180 days after the last dose of study treatment.

PHASE Ⅱ (DOSE EXTENSION)：

• Subjects are willing and able to provide written informed consent or where consent is provided by legally authorized representatives.
• Age ≥18 years old when signing the informed consent form.
• Patients with histologically or cytologically confirmed, locally advanced or metastatic solid tumors, which have failed on standard therapy, or are intolerable to 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 including esophagus adenocarcinomas, lung cancer, colorectal cancer, and biliary tract cancer.

• Only patients with tumor expressing CLDN 18.2 will be enrolled. The most recently available 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 deemed to be inappropriate for the confirmation of CLDN18.2 expression, a new biopsy must be performed to obtain the tumor sample to confirmation of CLDN18.2 expression.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Estimated life expectancy > 12 weeks.
• At least one measurable cancer lesion as defined by the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).
• Adequate organ function, evidenced by the following laboratory results:

• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.
• Platelet count ≥ 100 × 109/L.
• Hemoglobin ≥ 9.0 g/dL.
• Total bilirubin ≤ 1.5 × the upper limit of normal (ULN).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5× ULN (if liver metastases are present, ≤ 3 × ULN).
• Creatinine clearance (Ccr) ≥50 mL/minute as calculated using the modified Cockcroft-Gault equation.
• QTc prolongation to ≤ 480 millisecond (ms) (based on the average of 3 screening electrocardiograms) (QTc interval corrected by Fridericia's Correction Formula, QTcF = QT/(RR0.33).
• Echocardiographic LVEF (left ventricular ejection fraction) ≥ 50%.
• Female patients of childbearing potential, who are willing to use a highly effective method of birth control during the study and for at least 180 days following the last dose of study medication.

• Childbearing potential is defined as any female who has experienced menarche and does not meet the criteria for postmenopausal, which is defined as the past 12 months with no menses without an alternative medical cause or permanently sterilized (e.g., has undergone bilateral tubal occlusion/ligation, hysterectomy, bilateral oophorectomy, bilateral salpingectomy).
• A highly effective method of birth control is defined as one that results in a low failure rate (i.e., <1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or a vasectomized partner.
• Male patients with female sexual partners of childbearing potential are eligible for inclusion if they agree to use medically acceptable birth control for 180 days following the last dose of study medication. Sexual abstinence, vasectomy, or a condom used with a spermicide are medically acceptable birth control methods for males. Male subjects must agree not to donate sperm for a period of 180 days after the last dose of study treatment.

Exclusion criteria

• PHASE I (DOSE ESCALATION)：

• Prior severe allergic reaction or intolerance to a monoclonal antibody, including humanized or chimeric antibodies.
• Prior severe allergic reaction or intolerance to the Topoisomerase I Inhibitor or Topoisomerase Inhibitor-Based ADC (e.g: Fam-trastuzumab deruxtecan-nxki, Sacituzumab govitecan-hziy, Irinotecan, Topotecan) or any excipient in the XNW27011 formulation.
• Having any of the following medical conditions in the past or at present:

• Acquired or congenital immunodeficiency diseases or organ transplantation.
• Past myocardial infarction (within 6 months before the first administration), hospitalization for congestive heart failure within 12 months 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 (Systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg at rest).
• Concomitant diseases that will seriously endanger the safety of the subject or affect the completion of the tests, such as active gastrointestinal bleeding, active peptic ulcer, intestinal obstruction, intestinal paralysis, interstitial pneumonia, lung fibrosis, kidney failure, and uncontrolled diabetes(HbA1c>8%).
• History of or currently suffering from uncontrolled primary or metastasized brain tumors, except that the investigator believes that the disease has been stabilized in patients, or whose local treatment has ended.
• History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of the XNW27011.
• Past or current mental illness that is difficult to control.
• Human immunodeficiency virus (HIV) infection, syphilis infection, or active hepatitis B or C infection. Note: Syphilis infection refers to active syphilis or latent syphilis that requires treatment.
• Patients who have active infections that required systemic treatment within 2 weeks prior to the first dose of XNW27011.
• Clinically significant third spacing (large amount of pleural fluid or ascites, judged by treating physician) that is uncontrollable by drainage or other methods.
• Having any adverse event from prior anti-tumor treatments that have not yet recovered to Grade 0 or 1 per NCI-CTCAE v5.0 (except alopecia).
• History of treatment:

• Patients who have previously participated in clinical trials of other drugs within 4 weeks before the first dose of XNW27011.
• Received anti-tumor therapy (chemotherapy, radiotherapy, immunologic therapy or biological therapy,) within 3 weeks, prior to the first dose of XNW27011, or received small molecular targeted therapy, anti-tumor medicinal herb or proprietary Chinese traditional medicines within 2 weeks, or received palliative radiotherapy for bone metastases within 2 weeks, or received nitrosoureas or mitomycin C within 6 weeks.
• Received major surgical or interventional treatment within 4 weeks prior to the first dose of XNW27011, with the exception of tumor biopsy, puncture, etc.
• Received systemic steroid therapy for a long period of time (≥20 mg of prednisone/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 the first dose of XNW27011 can be selected).
• Received live vaccines within 4 weeks prior to the first dose of XNW27011 or plan to take any live vaccine during the study period.
• Received strong inhibitors or inducers of CYP3A4, or strong inhibitors of CYP2D6 within 2 weeks or five half-lives (whichever is shorter) of the inhibitor or inducer prior to the first dose of XNW27011.
• Women who are pregnant or breastfeeding, or women whose serum pregnancy test results are positive during the screening period (female patients who are infertile do not need to undergo a pregnancy test, e.g., female patients who underwent hysterectomy, bilateral tubal occlusion/ ligation, bilateral salpingectomy, or bilateral oophorectomy in the past, or women with resection or amenorrhea ≥12 months).
• Patients who have poor compliance and are not expected to cooperate to complete the study procedures, or who are deemed unsuitable to participate in the clinical research by the investigator. PHASE Ⅱ (DOSE EXTENSION)：

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• Prior severe allergic reaction or intolerance to a monoclonal antibody, including humanized or chimeric antibodies.
• Prior severe allergic reaction or intolerance to the Topoisomerase I Inhibitor or Topoisomerase Inhibitor-Based ADC (e.g: Fam-trastuzumab deruxtecan-nxki, Sacituzumab govitecan-hziy, Irinotecan, Topotecan) or any excipient in the XNW27011 formulation.
• Having any of the following medical conditions in the past or present:

• Acquired or congenital immunodeficiency diseases or organ transplantation.
• Past myocardial infarction (within 6 months before the first administration), hospitalization for congestive heart failure within 12 months 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 (Systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg at rest).
• Concomitant diseases that will seriously endanger the safety of the subject or affect the completion of the study, such as active gastrointestinal bleeding, active peptic ulcer, intestinal obstruction, intestinal paralysis, interstitial pneumonia, lung fibrosis, kidney failure, and uncontrolled diabetes (HbA1c>8%).
• Previously or currently suffering from uncontrollable primary or metastasized brain tumors, except that the investigator believes that the disease has been stabilized in patients, or whose local treatment has ended.
• History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of XNW27011.
• Past or current mental illness that is difficult to control.
• Human immunodeficiency virus (HIV) infection, syphilis infection, or active hepatitis B or C infection.

Note: Syphilis infection refers to active syphilis or latent syphilis that requires treatment.

• Patients who have active infections that required systemic treatment within 2 weeks prior to the first dose of XNW27011.
• Has multiple primary malignancies within 5 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, and other solid tumors curatively treated.
• Clinically significant third spacing (large amount of pleural fluid or ascites, judged by treating physician) that is uncontrollable by drainage or other methods.
• Having any adverse event from prior anti-tumor treatments that have not yet recovered to Grade 0 or 1 per NCI-CTCAE v5.0 (except alopecia).
• History of treatment:

• Patients who have previously been treated with ADCs or CAR-T targeting CLDN18.2, or participated in clinical trials of other drugs within 4 weeks before the first dose of XNW27011.
• Received anti-tumor therapy (chemotherapy, radiotherapy, immunologic therapyor biological therapy) within 3 weeks, prior to the first dose of XNW27011, or received small molecular targeted therapy, anti-tumor medicinal herb or proprietary Chinese traditional medicines within 2 weeks, or received palliative radiotherapy for bone metastases within 2 weeks, or received nitrosoureas or mitomycin C within 6 weeks.
• Have received major surgical or interventional treatment within 4 weeks prior to the first dose of XNW27011, with the exception for tumor biopsy, puncture, etc.
• Received systemic steroid therapy for a long period of time (≥20 mg of prednisone/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 the first dose of XNW27011 can be selected).
• Received live vaccines within 4 weeks prior to the first dose of XNW27011or planned to take any live vaccine during the study period.
• Received strong inhibitors or inducers of CYP3A4, or strong inhibitors of CYP2D6 within 2 weeks or five half-lives (whichever is shorter) of the inhibitor or inducer prior to the first dose of XNW27011.
• Women who are pregnant or breastfeeding, or women whose serum pregnancy test results are positive during the screening period (female patients who are infertile do not need to undergo a pregnancy test, e.g., female patients who underwent hysterectomy, bilateral tubal occlusion/ligation, bilateral salpingectomy, or bilateral oophorectomy in the past and women with resection or amenorrhea ≥12 months).
• Patients who have poor compliance and are not expected to cooperate to complete the study procedures, or who are deemed unsuitable to participate in the clinical research by the investigator.