Clinical Trial on the Protective Role of Vitamin B3 in Enhancing Immunotherapy for Bladder Cancer Patients

Korábbi kezelés

• Previous therapy directed against PD-1, PD-L1, PD-L2, CTLA-4 or any other antibody or drug targeting T-cell co-stimulation or checkpoint pathways.
• Systemic anticancer therapy or systemic immunomodulator (e.g. interferon, interleukin-2, TNF) within 28 days before enrolment.
• Prior radiotherapy to the bladder.
• Prior antitumour drug therapy, except:
  • ≥12 months since the last dose of systemic chemotherapy before study neoadjuvant therapy;
  • Intravesical chemotherapy or immunotherapy completed ≥1 week before study treatment.
• Major surgery or significant trauma within 28 days before enrolment (vascular-access placement and TURBT are not major surgery).
• Live vaccine within 28 days before enrolment (inactivated seasonal influenza vaccine is permitted; intranasal influenza vaccine is live and prohibited).
• Long-term high-dose corticosteroids or other immunosuppressants that, in the investigator's opinion, would interfere with study treatment.
• History of immunodeficiency (including HIV positivity or other acquired/congenital immunodeficiencies), or prior allogeneic stem-cell or solid-organ transplantation (Appendix 3).

Más betegség

• Active autoimmune disease requiring systemic therapy that, in the investigator's opinion, would interfere with study treatment.
• Clinically significant abnormalities that could affect treatment, including electrolyte disturbance (K, Na, Ca), hypoalbuminaemia, interstitial lung disease, non-infectious pneumonitis, or other uncontrolled systemic diseases (e.g. diabetes, hypertension, cardiovascular disease such as severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, or clinically significant ventricular arrhythmia within 6 months).
• Untreated chronic HBV infection with HBV-DNA ≥500 IU/mL (2,500 copies/mL) or HBsAg carrier status. Patients with inactive HBsAg carriage or stable active HBV on antiviral therapy with HBV-DNA < 500 IU/mL may enrol. HBV-DNA testing is required only for anti-HBc-positive patients.
• Active HCV infection. Patients who are anti-HCV-negative, or anti-HCV-positive but HCV-RNA-negative, may enrol. Anti-HCV-positive patients must have HCV-RNA testing.
• Known hypersensitivity to other monoclonal antibodies.
• Known hypersensitivity to any study drug or excipient.
• Any condition (medical or substance abuse) that could impede study-drug administration, confound interpretation of results, or place the patient at high risk of complications.

Laborértékek

• Unresolved toxicities from prior therapy that have not returned to baseline or stabilised, unless considered by the investigator not to pose a safety risk (e.g. alopecia, neuropathy, certain laboratory abnormalities).

Egyéb

• Patients meeting any of the following are ineligible:

• The patient voluntarily agrees to participate, is able to provide written informed consent, and is willing and able to comply with the protocol and schedule of assessments.
• Aged ≥18 years on the date of signing the informed-consent form (ICF).
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix 1).
• Residual tumour after TURBT and histologically confirmed urothelial carcinoma of the bladder staged cT2-T4a N0 M0 by AJCC 8th edition imaging; for mixed-histology tumours, the urothelial component must be predominant (≥50 %).
• An infection occurring from 30 days to 1 day before the first dose of immuno-chemotherapy that, in the judgement of the attending physician, required oral or intravenous bactericidal antibiotics and met any of the following diagnostic criteria:
  • Clinical features (e.g. ≥38.3 °C or sustained ≥38 °C for ≥1 h with chills, local pain, dysuria, etc.) plus laboratory evidence (WBC > 10 × 10⁹/L or < 4 × 10⁹/L, neutrophilia / neutropenia, markedly elevated CRP) consistent with bacterial infection;
  • Abnormal urinalysis suggestive of urinary-tract infection (e.g. WBC > 10/HPF, bacteria seen on high-power field, nitrite positive) with pathogen confirmed by urine culture;
  • Infection confirmed by imaging or other microbiological tests (e.g. blood culture, nasopharyngeal swab, sputum culture).
  • Permitted bactericidal antibiotics (oral or IV) include but are not limited to:
  • β-lactams (penicillins, cephalosporins, carbapenems);
  • Glycopeptides (vancomycin, teicoplanin);
  • Quinolones (levofloxacin, ciprofloxacin);
  • Aminoglycosides (gentamicin, streptomycin).
• Adequate organ function, documented within ≤14 days before enrolment:
  • No growth-factor support ≤14 days before sampling and: i. Absolute neutrophil count ≥1.5 × 10⁹/L; ii. Platelets ≥90 × 10⁹/L; iii. Haemoglobin ≥90 g/L; b. INR or aPTT ≤1.5 × ULN; c. Total bilirubin ≤1.5 × ULN (≤3 × ULN for Gilbert's syndrome or isolated indirect hyper-bilirubinaemia of extra-hepatic origin); d. AST, ALT and alkaline phosphatase ≤2.5 × ULN; e. Pulmonary function adequate to tolerate major abdominal surgery.
• Considered cisplatin-eligible by the investigator. Patients deemed cisplatin-ineligible must meet ≥1 of: ECOG > 1 or Karnofsky 60-70 %; creatinine clearance < 60 mL/min; NCI-CTCAE v5.0 grade ≥2 hearing loss; NCI-CTCAE v5.0 grade ≥2 peripheral neuropathy; New York Heart Association class III or IV heart failure.
• Women of child-bearing potential agree to use highly effective contraception during the study and for ≥120 days after the last dose of tislelizumab or chemotherapy (whichever is later) and have a negative urine or serum pregnancy test ≤7 days before enrolment. Non-sterilised men likewise agree to use highly effective contraception for the same period (Appendix 5).