Study of XNW5004 Tablets in Advanced Prostate Cancer

This study consists of two phases. The first phase (Phase Ib) is a safety lead-in study of XNW5004 in combination with anti-tumor therapy; the second phase (Phase II) is a dose expansion study of XNW5004 in combination with anti-tumor therapy.

Phase Ib is a non-randomized, open-label study. Given the differences in mechanism of action, pharmacokinetic profiles, and toxicity profiles when XNW5004 is combined with different anti-tumor agents, the safety lead-in will be conducted independently for each combination cohort.

Upon completion of the Cycle 1 safety evaluation for the corresponding cohort in Phase Ib, the Phase II study will be initiated. Phase II is a randomized, open-label, dose expansion study. A preliminary design of 5 cohorts will further evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of XNW5004 in combination with anti-tumor therapy in participants with advanced prostate cancer.

The study process includes a screening period, a treatment period, and a follow-up period. Eligible participants after screening will enter the treatment period and receive therapy according to the combination regimen of their assigned cohort, until disease progression, death, withdrawal of informed consent, intolerable toxicity, or any other condition that the investigator deems necessary for study discontinuation.

Participants will undergo PK and PD blood sampling at designated time points, and relevant anti-tumor efficacy assessments will be performed.

• Signed written informed consent prior to initiation of any study activity/procedure;
• Male, ≥18 years of age;
• Expected survival ≥ 3 months;
• ECOG performance status score of 0-1;
• Histologically or cytologically confirmed prostate adenocarcinoma of a single pathological type, excluding neuroendocrine carcinoma or small cell carcinoma;
• Bone metastatic lesions confirmed by bone scan, or soft tissue metastatic lesions confirmed by CT/MRI, with at least one evaluable lesion according to RECIST 1.1 and PCWG3 criteria. *Note:* Isolated regional lymph node metastasis alone does not qualify for study participation;
• Continuous luteinizing hormone-releasing hormone agonist (LHRHa) or antagonist therapy (medical castration), or prior bilateral orchiectomy (surgical castration); participants who have not undergone bilateral orchiectomy must plan to maintain effective LHRHa therapy throughout the entire study period;
• Castrate level of testosterone at screening (≤50 ng/dL or 1.7 nmol/L);
• Disease progression at screening, defined as meeting one or more of the following three criteria while receiving castration therapy: ① PSA progression, defined as PSA >1 ng/mL with at least 2 consecutive PSA elevations separated by ≥1 week; ② Disease progression per RECIST 1.1; ③ Bone disease progression per PCWG3 criteria, defined as ≥2 new lesions identified on bone scan;
• Prior antitumor therapy meets the following requirements:

• Phase Ib:

• Cohort 1 (combination with abiraterone + prednisone for mCRPC):* Prior failure of novel hormonal therapy other than abiraterone acetate - defined as disease progression during treatment with novel hormonal therapy other than abiraterone (for at least 12 weeks) in the setting of mCSPC or mCRPC, or disease progression during treatment with novel hormonal therapy other than abiraterone (for at least 12 weeks) in the non-metastatic setting or within 3 months after completing such therapy; disease progression is defined as per Inclusion Criterion 9.
• Cohort 2 (combination with docetaxel + prednisone for mCRPC):* Metastatic castration-resistant prostate cancer with prior failure of at least one novel hormonal therapy; failure of novel hormonal therapy is defined as per Cohort 1.
• Phase II:

• Cohort 1 (combination with abiraterone + prednisone for mCRPC):* Prior failure of novel hormonal therapy other than abiraterone acetate - defined as disease progression during treatment with novel hormonal therapy other than abiraterone (for at least 12 weeks) in the setting of mCSPC or mCRPC, or disease progression during treatment with novel hormonal therapy other than abiraterone (for at least 12 weeks) in the non-metastatic setting or within 3 months after completing such therapy; disease progression is defined as per Inclusion Criterion 9.
• Cohort 2 (combination with abiraterone + prednisone for mCSPC):No prior systemic antitumor therapy other than androgen deprivation therapy (ADT) and first-generation antiandrogens. Prior ADT (medical or surgical castration) for up to 3 months is allowed, with no evidence of radiographic disease progression or PSA elevation prior to Cycle 1 Day 1.
• Cohort 3 (combination with docetaxel + prednisone for mCRPC):Metastatic castration-resistant prostate cancer with prior failure of at least one novel hormonal therapy; failure of novel hormonal therapy is defined as per Cohort 1.
• Cohort 4 (combination with enzalutamide for mCSPC):No prior systemic antitumor therapy other than androgen deprivation therapy (ADT) and first-generation antiandrogens. Prior ADT (medical or surgical castration) for up to 3 months is allowed, with no evidence of radiographic disease progression or PSA elevation prior to Cycle 1 Day 1.
• Cohort 5 (combination with other agents):Participants with advanced prostate cancer who have failed prior therapy other than the agent class of interest (to be specified via protocol amendment prior to cohort initiation).
• Participant laboratory values meet the following requirements:

• Hepatic function assessment:

• Alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases);
• Aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases);
• Total bilirubin ≤ 1.5 × ULN (≤ 3.0 × ULN for Gilbert's syndrome).
• Renal function assessment:**

• Creatinine clearance ≥ 60 mL/min (per Cockcroft and Gault formula, Appendix 20.3), or serum creatinine ≤ 1.5 × ULN.
• Hematology assessment:**

• Absolute neutrophil count (ANC) ≥ 1.0 × 10⁹/L (no granulocyte colony-stimulating factor [G-CSF] within 1 week, and no long-acting G-CSF within 2 weeks prior to screening CBC) - for non-docetaxel combination cohorts; Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L (no G-CSF within 1 week, and no long-acting G-CSF within 2 weeks prior to screening CBC) - for docetaxel combination cohorts;
• Platelets ≥ 75 × 10⁹/L (no platelet transfusion and no thrombopoietin [TPO] within 1 week prior to screening CBC);
• Hemoglobin ≥ 8 g/dL (80 g/L) (no red blood cell transfusion and no erythropoietin [EPO] within 1 week prior to screening CBC).
• Coagulation assessment:

• Prothrombin time (PT) < 1.5 × ULN, or international normalized ratio (INR) < 1.5 × ULN; if the participant is currently on anticoagulant therapy, INR ≤ 3 × ULN.
• Must agree to use adequate contraception from study initiation through at least 6 months after the last dose of study drug, and must refrain from sperm donation;
• Able to comply with all study procedures as judged by the investigator.

Exclusion criteria

Participants meeting any of the following criteria will not be eligible for enrollment in this study:

• Prior antitumor therapy meets the following conditions:

• Phase Ib:

• Cohort 1: Prior treatment with abiraterone or cytotoxic chemotherapy (including but not limited to antibody-drug conjugates [ADCs] with cytotoxic payload). *Note:* Docetaxel use during the hormone-sensitive setting is allowed, provided there was no treatment failure or disease progression during therapy or within 3 months after completion.
• Cohort 2: Prior cytotoxic chemotherapy (including but not limited to ADCs with cytotoxic payload) at any stage of prostate cancer. *Note:* Docetaxel use during the hormone-sensitive setting is allowed, provided there was no treatment failure or disease progression during therapy or within 3 months after completion.
• Phase II:

• Cohort 1: Prior treatment with abiraterone or cytotoxic chemotherapy (including but not limited to ADCs with cytotoxic payload). *Note:* Docetaxel use during the hormone-sensitive setting is allowed, provided there was no treatment failure or disease progression during therapy or within 3 months after completion.
• Cohort 2:Participants must be treatment-naïve in the metastatic castration-sensitive prostate cancer (mCSPC) setting; i.e., participants must not have received any cytotoxic chemotherapy (including but not limited to ADCs with cytotoxic payload), with the exception that first-generation antiandrogen (ADT) therapy is allowed during the mCSPC stage.
• Cohort 3:Participants must not have received any cytotoxic chemotherapy (including but not limited to ADCs with cytotoxic payload). *Note:* Docetaxel use during the hormone-sensitive setting is allowed, provided there was no treatment failure or disease progression during therapy or within 3 months after completion.
• Cohort 4: Participants must be treatment-naïve in the metastatic castration-sensitive prostate cancer (mCSPC) setting; i.e., participants must not have received any cytotoxic chemotherapy (including but not limited to ADCs with cytotoxic payload), with the exception that first-generation antiandrogen (ADT) therapy is allowed during the mCSPC stage.
• Prior treatment with agents similar to or targeting the same pathway as the study drug (including but not limited to tazemetostat, EZH1/2 inhibitors, and EED inhibitors);
• Received chemotherapy, immunotherapy, definitive radiotherapy, targeted therapy, anti-tumor traditional Chinese medicine, or other anti-tumor therapies within 4 weeks or 5 half-lives (whichever is shorter) prior to the first dose; palliative radiotherapy within 2 weeks prior to the first dose;
• Planned receipt of any other anti-tumor therapy during the study period;
• Received any other investigational product not yet approved in the study region within 28 days prior to the first dose of this study (i.e., last dose of investigational product within 28 days of the first study drug dose);
• Presence of central nervous system (CNS) metastases; history of or concurrent CNS conditions including but not limited to epilepsy, paralysis, stroke, severe brain injury, Alzheimer's disease, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis, spinal cord compression, or cauda equina syndrome (with the exception of stroke that was adequately treated and stable for ≥12 months prior to first dose, or asymptomatic/untreated lacunar infarction);
• Severe bone damage due to tumor bone metastases as judged by the investigator, including poorly controlled severe bone pain, pathological fractures at critical sites occurring within the last 6 months or expected in the near future, and spinal cord compression;
• History of other malignancy within 3 years prior to enrollment that does not meet clinical cure criteria. Exceptions: basal cell carcinoma or squamous cell carcinoma of the skin that has been locally treated and cured, superficial bladder cancer, ductal carcinoma in situ of the breast, and papillary thyroid carcinoma;
• Poorly controlled bladder outlet obstruction or urinary incontinence as judged by the investigator;
• Impaired cardiac function or clinically significant cardiac disease, including any of the following:

• Acute myocardial infarction or unstable angina ≤ 6 months prior to first dose;
• Congestive heart failure (New York Heart Association [NYHA] Class III or IV), left ventricular ejection fraction (LVEF) < 50%;
• Uncorrected serious arrhythmia, hypertension ≥ 150/100 mmHg;
• Prolonged QTc interval (defined as >450 ms for males, >470 ms for females) per Fridericia's formula (see Appendix 20.4);
• History of other major cardiovascular disease (e.g., valve replacement, coronary artery bypass grafting, etc.);
• Active systemic severe infection: a washout period of at least 2 weeks is required after completion of antifungal therapy (whether intravenous or oral); at least 1 week washout after completion of other intravenous anti-infective therapy; other oral anti-infective therapy must meet discontinuation criteria and be stopped prior to the first study dose;
• History of tuberculosis infection within 1 year prior to enrollment, or history of active tuberculosis infection more than 1 year ago without adequate anti-tuberculosis treatment;
• Known hypersensitivity to the study drug or its active ingredients or excipients;
• Use of known moderate or strong CYP3A inducers or inhibitors within 14 days prior to the first dose (see Appendix 20.5);
• Active autoimmune and inflammatory diseases, such as systemic lupus erythematosus, psoriasis requiring systemic therapy, rheumatoid arthritis, inflammatory bowel disease, and Hashimoto's thyroiditis; with the exception of Type 1 diabetes mellitus, hypothyroidism controlled solely by replacement therapy, hyperthyroidism stable on medication, and skin conditions not requiring systemic therapy (e.g., vitiligo, localized psoriasis);
• History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis requiring steroid therapy, or any evidence of clinically active ILD;
• Known gastrointestinal (GI) function impairment or GI conditions that may significantly affect the absorption or metabolism of oral medications; abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to the first dose;
• Human immunodeficiency virus (HIV) positive, or syphilis (Anti-TP) positive (not excluded if non-treponemal syphilis test is negative and the investigator determines syphilis has been cured);
• Known acute or chronic active hepatitis B (HBsAg positive or HBcAb positive with HBV DNA ≥ 200 IU/mL or ≥ 10³ copies/mL), or acute or chronic active hepatitis C (HCV antibody positive with HCV RNA positive);
• Toxicities from prior anti-tumor therapy that have not resolved (not recovered to ≤ Grade 1 per NCI-CTCAE Version 6.0). Exceptions include other toxicities that the investigator deems do not affect participant safety assessment (e.g., alopecia);
• Symptomatic pleural effusion, ascites, or pericardial effusion that is poorly controlled despite repeated treatment;
• Prior allogeneic tissue or solid organ transplantation;
• Major surgery within 4 weeks prior to dosing, or planned major surgery during the study period (excluding procedures such as puncture or lymph node biopsy);
• Received live virus vaccine (including live attenuated vaccine) within 28 days prior to dosing; inactivated vaccines are allowed;
• Baseline bone scan showing a "superscan" pattern that precludes assessment of new bone metastases;
• Any other condition that, in the investigator's judgment, makes the participant unsuitable for enrollment.