A Phase II Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of YL201 in Patients With mCRPC

Inclusion criteria

• Subjects who understand relevant information of the study prior to initiation of the study and voluntarily sign and date on the ICF.
• Age ≥ 18 years.
• Patients should meet the following conditions to be enrolled:

• Histologically or cytologically confirmed prostate cancer. Note: The primary histological classification indicated by biopsy should be adenocarcinoma;
• Meeting the following criteria for clinical diagnosis of mCRPC:

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• Subjects who understand relevant information of the study prior to initiation of the study and voluntarily sign and date on the ICF.
• Age ≥ 18 years.
• Patients should meet the following conditions to be enrolled:

• Histologically or cytologically confirmed prostate cancer. Note: The primary histological classification indicated by biopsy should be adenocarcinoma;

• Meeting the following criteria for clinical diagnosis of mCRPC:

√Testosterone level after castration (a serum testosterone level of <50 ng/dl or 1.7 nmol/L);

• Serum prostate specific antigen (PSA) progression (PSA > 1 ng/mL and 2 consecutive increases in PSA with at least a 1-week interval >50% from baseline), or PD by imaging (≥ 2 new bone lesions suggested by a bone scan according to PCWG3 criteria; and/or progression of soft tissue lesions suggested by computed tomography (CT) or nuclear magnetic resonance imaging (MRI) according to RECIST v1.1); meeting either or both criteria;
• Persistent luteinizing hormone-releasing hormone (LHRH) analogue castration (medical castration) or prior bilateral orchiectomy (surgical castration); surgical castration should be performed at least 3 months prior to enrollment, and medical castration is required from at least 3 months prior to the first dose and throughout the study for subjects not yet undertake bilateral orchiectomy; • Patients with progression on or intolerance to at least one prior novel hormone therapy (NHT) (e.g., enzalutamide, abiraterone, darolutamide, apalutamide, or rezvilutamide); • Prior therapy with no more than 2 lines of chemotherapy is allowed; • Patients with known previous prostate adenocarcinoma with a documented BRCA1/2 (germline or somatic) mutation should have received poly ADP ribose polymerase (PARP) inhibitor therapy (if available and tolerated);
• Patients with metastatic lesions confirmed by CT, MRI, or bone scan imaging within 28 days prior to the first dose.
• Patients with archived or fresh tumor tissue samples. Patients who cannot provide tumor samples or cannot provide sufficient samples may be enrolled in this study after considering specific circumstances and discussions with the Sponsor.

• Fresh tumor tissue samples (formalin-fixed, paraffin-embedded (FFPE) tumor blocks or FFPE sections) should be provided for retrospective detection of B7H3 expression by the central laboratory using the immunohistochemistry [IHC] method; if fresh tumor tissue samples are not available, FFPE tumor blocks previously archived are acceptable, and fresh FFPE sections should be prepared within 2 weeks.
• Eastern cooperative oncology group performance status (ECOG PS) score of 0 or 1.
• The function of organs and bone marrow meets the requirements within 7 days prior to the first dose, which is defined as follows:

• Hemoglobin (Hb) ≥ 90 g/L (no blood transfusion or erythropoietin treatment within 14 days prior to the first dose);

• Absolute neutrophil count (ANC) ≥ 1.5×109/L (no treatment with granulocyte colony stimulating factor or granulocyte-macrophage colony stimulating factor within 14 days prior to the first dose);

• Platelet count (PLT) ≥ 100×109/L (no platelet transfusion, thrombopoietin, or interleukin-11 within 14 days prior to the first dose);

• Total bilirubin (TBIL) ≤ 1.5×upper limit of normal (ULN) in the absence of obvious liver metastasis, or ≤ 3×ULN in the presence of liver metastasis;

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3×ULN in the absence of obvious liver metastasis or ≤ 5×ULN in the presence of liver metastasis;

• Serum albumin (ALB) ≥ 30 g/L;

• Creatinine clearance calculated using Cockcroft-Gault formula ≥ 50 mL/min or the creatinine ≤ 1.5×ULN;
• Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5×ULN, except for patients who are on anticoagulant therapy. In this case, a stable anticoagulant regimen should be maintained with APTT and INR controlled within the range deemed appropriate by the investigator.
• Patients must agree to adopt highly effective contraceptive measures from screening, throughout the study period, and within at least 6 months after the last dose of the investigational drug.
• Expected survival ≥ 6 months.
• Be capable of and willing to comply with the visits and procedures stipulated in the study protocol.

Exclusion criteria

• Previously treated with drugs targeting B7H3.
• Currently participating in another clinical study, unless it is an observational (non-interventional) clinical study, or the patient is at the follow-up period of an interventional study.
• Previously treated with topoisomerase I inhibitors or ADC therapy composed of topoisomerase I inhibitors.
• The washout period of the previous anti-tumor therapy is considered insufficient.
• Patients received major surgery.
• Prior treatment with allogeneic bone marrow transplantation or solid organ transplantation.
• Prior treatment with glucocorticoids for more than 28 consecutive days within 28 days prior to the first dose of the investigational drug.
• Patients received any live vaccine within 4 weeks prior to the first dose of the investigational drug, or plan to receive live vaccine during the study period.
• Have pathological long bone fracture, or the risk of pathological long bone fracture.
• Have meningeal metastasis or cancerous meningitis.
• Have uncontrolled bladder outlet obstruction or urinary incontinence.
• Have brain metastasis or spinal cord compression.
• Patients with uncontrolled or clinically significant cardiovascular diseases.
• Clinically significant complicated pulmonary disorders.
• Diagnosed with Gilbert's syndrome.
• Accompanying uncontrolled effusion in the third space requiring repeated drainage.
• Medical history of gastrointestinal perforation and/or fistula within 6 months prior to the first dose, or active gastric and duodenal ulcers, ulcerative colitis, or other gastrointestinal diseases that may cause hemorrhage or perforation in the opinion of the investigator.
• Active serious infection (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] ≥ 3) within 4 weeks prior to the first dose.
• Known human immunodeficiency virus (HIV) infection.
• Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
• Diagnosed with the other malignancies that may change the expected survival or affect the response evaluation.
• Unresolved toxicity of previous anti-tumor therapy.
• History of severe hypersensitivity to inactive ingredients in the drug substance and drug product or other monoclonal antibodies.
• Have any diseases, medical conditions, organ system dysfunction, or social conditions that may interfere with the subject ability to sign the ICF, adversely affect the subject ability to cooperate and participate in the study, or affect the interpretation of study results, including but not limited to mental illness or substance/alcohol abuse, in the opinion of the investigator.