Tislelizumab in Combination With Bevacizumab and Capecitabine in Advanced Solid Tumors With Evaluation in Immunotherapy-Resistant and Central Nervous System Disease

Inclusion Criteria:

Patients are eligible for enrolment if they meet all applicable general inclusion criteria and, where relevant, the cohort-specific inclusion criteria.

1. General Inclusion Criteria

   * Age 21 years or older at the time of informed consent.
   * Histologically or cytologically confirmed advanced or metastatic solid tumor.
   * Patients must have received at least one prior line of standard systemic therapy for locally advanced/unresectable or metastatic disease, OR be ineligible for, intolerant of, or have declined standard-of-care therapy, with the specific reason documented in the source records.
   * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
   * Estimated life expectancy of at least 12 weeks.
   * At least one evaluable (measurable or non-measurable) lesion as defined by RECIST version 1.1, unless otherwise specified for a disease-specific cohort.
   * Recovery to Grade 1 or baseline from acute toxicities of prior anti-cancer therapy, except for alopecia, vitiligo, or other toxicities deemed not clinically significant by the investigator.
   * Adequate organ and marrow function within 14 days prior to first dose of study treatment, defined as follows:

     1. Absolute neutrophil count ≥1.5 × 10\^9/L
     2. Platelet count ≥100 × 10\^9/L
     3. Haemoglobin ≥9.0 g/dL
     4. Total bilirubin \<1.5 × upper limit of normal, except in patients with known Gilbert's syndrome, in whom total bilirubin up to 3.0 × upper limit of normal is permitted provided direct bilirubin is within normal limits
     5. AST and ALT \<2.5 × upper limit of normal, or \<5 × upper limit of normal in the presence of liver metastases
     6. Calculated creatinine clearance ≥50 mL/min (calculated using the Cockcroft-Gault formula)
     7. Urine protein dipstick \<2+, or if urine dipstick is 2+ or greater, 24-hour urine protein \<1 g per 24 hours
   * Adequately controlled blood pressure (systolic \<150mmHg, diastolic \<100mmHg) with or without anti-hypertensive medication.
   * Able to swallow and retain oral medication.
   * Able to understand and willing to sign written informed consent.
   * Willing and able to comply with study visits, treatment plan, laboratory tests, imaging, and other protocol-required procedures.
   * Prior exposure to immune checkpoint inhibitors, anti-angiogenic therapy, or fluoropyrimidines is permitted, unless prohibited by cohort-specific criteria.
2. TNBC Cohort Inclusion Criteria

   * Histologically confirmed triple-negative breast cancer, defined as estrogen receptor \<1%, progesterone receptor \<1%, and HER2-negative according to current ASCO/CAP guidelines.
   * Metastatic or unresectable locally advanced disease not amenable to curative treatment.
   * PD-L1-negative disease, defined as combined positive score (CPS) \<10 using an approved assay.
   * Candidate for first-line systemic therapy for metastatic disease.
   * Patients must have measurable or non-measurable but evaluable disease per RECIST v1.1.
   * Patients without measurable disease may be enrolled provided they have unequivocal non-measurable disease that can be adequately assessed or disease status on serial radiologic evaluations, in the opinion of the investigator.
   * Prior neoadjuvant or adjuvant chemotherapy is permitted.
   * Prior immune checkpoint inhibitor therapy in the neoadjuvant or adjuvant setting is permitted, provided it was completed at least 12 months prior to start of study treatment.
   * Prior capecitabine is permitted only in the adjuvant setting, provided it was completed at least 12 months prior to start of study treatment.
   * Patients with prior CNS disease are eligible only if CNS disease is clinically controlled, defined as asymptomatic or minimally symptomatic, does not require corticosteroids and does not require ongoing CNS-directed therapy.
3. CNS Cohort Inclusion Criteria

   * Histologically or cytologically confirmed advanced solid tumor.
   * Progressive brain metastases.
   * At least one measurable CNS lesion.
   * Leptomeningeal disease is allowed.
   * Patients receiving corticosteroids for management of CNS disease or CNS-related symptoms are eligible provided the corticosteroid dose is stable or decreasing for at least 7 days prior to first dose of study treatment.
   * Patients with driver mutations (e.g., EGFR-mutant or ALK-rearranged NSCLC, HER2+ metastatic breast cancer) must have received at least one prior line of matched systemic therapy, unless such therapy is contraindicated, not tolerated, unavailable, or the patient is otherwise unsuitable in the investigator's judgment.
4. HR-Positive/HER2-Negative Cohort Inclusion Criteria

   * Histologically confirmed hormone receptor-positive (defined as ER\>1% or PR\>1%), HER2-negative metastatic or unresectable locally advanced breast cancer not amenable to curative treatment.
   * Patients must have measurable or non-measurable but evaluable disease per RECIST v1.1.
   * Patients without measurable disease may be enrolled provided they have unequivocal non-measurable disease that can be adequately assessed or disease status on serial radiologic evaluations, in the opinion of the investigator.
   * Prior failure of at least one line of endocrine therapy in the advanced or metastatic setting, unless deemed endocrine-resistant in the opinion of the investigator.
   * Up to one prior line of palliative chemotherapy is permitted.
   * If prior capecitabine was given, it must not have been administered in the metastatic setting and must have been completed \>12 months prior to study entry.
   * Any CNS disease must be clinically controlled, defined as asymptomatic or minimally symptomatic, must not require corticosteroids, and must not require ongoing CNS-directed therapy.

Exclusion Criteria:

Patients will be excluded if they meet any applicable general exclusion criterion or any relevant cohort-specific exclusion criterion.

1. General Exclusion Criteria

   * Treatment with an investigational agent within 14 days prior to first dose of study treatment.
   * Known hypersensitivity or contraindication to tislelizumab, bevacizumab, capecitabine, fluoropyrimidines, or any excipients of the study drugs.
   * Known clinically significant dihydropyrimidine dehydrogenase deficiency.
   * Uncontrolled or clinically unstable CNS disease, including poor performance status attributable to CNS disease, ongoing requirement for escalating corticosteroids, uncontrolled seizures, or rapid neurologic deterioration.
   * Clinically significant cardiovascular disease, including uncontrolled hypertension, unstable angina, clinically significant arrhythmia, myocardial infarction, or stroke that is of clinical concern in the opinion of the investigator.
   * Significant bleeding risk or recent clinically significant hemorrhage.
   * History of gastrointestinal perforation, fistula, or intra-abdominal abscess within 6 months prior to first dose, or other conditions conferring high risk in the opinion of the investigator.
   * Non-healing wound, active ulcer, or untreated fracture.
   * Active infection requiring systemic therapy.
   * Active autoimmune disease requiring systemic immunosuppressive treatment within the past 2 years, with exceptions such as replacement therapy or other conditions judged unlikely to recur.
   * Current use of systemic immunosuppressive medication, excluding physiologic corticosteroid replacement or other permitted low-dose steroids.
   * Active pneumonitis or interstitial lung disease requiring treatment, or other clinically significant pulmonary condition that, in the opinion of the investigator, would increase the risk of study treatment.
   * Other active malignancy requiring treatment or likely to interfere with assessment of study endpoints, in the opinion of the investigator.
   * Pregnancy or breastfeeding.
   * Any serious medical, psychiatric, or social condition that, in the opinion of the investigator, would compromise patient safety, interfere with study participation, or confound interpretation of study results.
2. TNBC Cohort Exclusion Criteria

   * Prior systemic therapy for metastatic TNBC.
   * Prior capecitabine in the metastatic setting.
   * Progressive CNS disease. Patients with progressive CNS disease should be enrolled into the CNS cohort instead.
3. CNS Cohort Exclusion Criteria

   * Severely symptomatic or clinically unstable CNS disease, including rapid neurologic deterioration, uncontrolled seizures, or requirement for rapidly escalating corticosteroids.
   * CNS disease requiring immediate neurosurgical intervention or urgent radiation therapy, in the opinion of the investigator.
   * Stereotactic radiosurgery (SRS) including gamma knife, within 7 days before the first dose of study treatment.
   * Whole brain radiotherapy (WBRT) within 21 days before the first dose of study treatment.
   * Use of checkpoint inhibitor, bevacizumab, and/or capecitabine within 6 months before the first dose of study treatment.
4. HR-Positive/HER2-Negative Cohort Exclusion Criteria

   * More than one prior line of palliative chemotherapy.
   * Progressive CNS disease. Patients with progressive CNS disease should be enrolled into the CNS cohort instead.