An Phase III Study, Multicenter，Randomized Controlled Trail to Determine the Safety and Efficacy of the Combination of Tislelizumab With Cisplatin and Gemcitabine, With or Without Trilaciclib for Patients With Untreated Unresectable and Metastatic Urothelial Carcinoma.

Sun Yat-sen University

Status and phase: Not yet enrolling; Phase 3

Conditions: Bladder Cancer

Treatments: Drug: Tislelizumab, Cisplatin, Gemcitabine and Trilaciclib; Drug: Tislelizumab, Cisplatin, Gemcitabine

Study type: Interventional

Funder types: Other

Identifiers

NCT06364904

SYSKY-2024-123-02

Details and patient eligibility

About

The aim of this study is to see whether the Trilaciclib is safe and effective in slowing down the growth of bladder cancer in patients while taking chemoimmunotherapy.

Enrollment: 210 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Voluntarily participate in this study, able to provide written informed consent and can understand and agree to comply with the requirements of the study and schedule of assessments.

2. Participants diagnosed histologically or cytologically with locally advanced or metastatic urothelial carcinoma (UC) of the renal pelvis, ureter, bladder, or urethra. Eligible subjects for inclusion are those with a mixed histologic type, as assessed by the investigator, with urothelial component >50% and plasmacytoid subtype <10%. Patients with histologically confirmed and radiologically assessed locally advanced or metastatic urothelial carcinoma of the urinary tract.

3. Participants judged by the investigator to be tolerant of platinum-based therapy. Participants intolerant to platinum chemotherapy must meet at least one of the following criteria: ECOG performance status >1 or Karnofsky performance status 60% to 70%; creatinine clearance less than 60 ml/min; hearing loss ≥ Grade 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5; peripheral neuropathy ≥ Grade 2 according to NCI-CTCAE version 5; New York Heart Association Class III or IV heart failure.

4. Must provide surgical or biopsy tumor tissue samples, and concurrent submission of relevant pathology reports is required. Participants are able to submit fresh surgical tissue or submit pathology slides for examination.

5. ECOG Performance Status 0 or 1

6. The participants must have well-functioning organ systems, as measured by the following screening laboratory values (obtained within ≤14 days before enrollment):

   a. When screening for the following parameters, participants must not have used growth factor support within ≤14 days before sample collection: i. Neutrophil absolute count ≥ 1.5x10^9/L ii. Platelets ≥ 90x10^9/L iii. Hemoglobin ≥ 90g/L b. International normalized ratio or activated partial thromboplastin time ≤ 1.5 times the upper limit of normal (ULN) c. Calculated creatinine clearance ≥ 50 mL/min d. Serum total bilirubin ≤ 1.5×ULN (if Gilbert's syndrome or indirect bilirubin concentration indicates extrahepatic elevation, should be ≤ 3×ULN) e. AST, ALT, and alkaline phosphatase ≤ 2.5×ULN

7. Women who are not pregnant or not of childbearing potential must be willing to use effective contraception during the study and for ≥120 days after the last dose of toripalimab monotherapy or chemotherapy (whichever occurs later). Additionally, they must have a negative urine or serum pregnancy test result within ≤7 days before enrollment. Non-sterilized men must be willing to use effective contraception during the study and for ≥120 days after the last dose of toripalimab monotherapy or chemotherapy (whichever occurs later).

8. According to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, at least one participant with measurable lesions is required.

9. Participants with an expected survival of ≥3 months.

Exclusion criteria

1. Known active or untreated central nervous system (CNS) metastases and/or carcinomatous meningitis. For patients with previously treated brain metastases, enrollment is not allowed if there has been CNS disease stability for at least 4 weeks before the first dose of study treatment and discontinuation of corticosteroid therapy for brain metastases for at least 2 weeks before the start of study treatment.

2. Prior treatment with therapies targeting PD-1, PD-L1, PD-L2, CTLA-4, or other agents specifically targeting T-cell co-stimulation or checkpoint pathways.

3. Receipt of other approved systemic anticancer therapy or systemic immunomodulatory agents (including but not limited to interferons, interleukins, and tumor necrosis factor) within 28 days before enrollment.

4. Prior radiotherapy for bladder cancer.

5. Prior systemic treatment for tumors, except:

   1. For patients previously treated with systemic chemotherapy, a treatment-free interval of at least 12 months from the last treatment to the start of drug treatment.
   2. Local intravesical chemotherapy or immunotherapy, completed at least 1 week before the start of study treatment.

6. Major surgery or significant trauma within 28 days before enrollment (placement of vascular access device and transurethral resection of bladder tumor [TURBT] are not considered major surgery).

7. Severe chronic or active infection requiring systemic antibacterial, antifungal, or antiviral therapy within 14 days before enrollment (HBV infection is excluded according to exclusion criterion 11).

8. Receipt of live vaccines within 28 days before enrollment (seasonal injections of influenza vaccine are usually inactivated vaccines and are allowed. Nasal vaccines are live vaccines and are not allowed).

9. Active autoimmune diseases requiring systemic treatment, as determined by the investigator, which could affect the safety of study treatment.

10. Long-term use of high-dose steroids or other immunosuppressive agents, as determined by the investigator, which could affect the safety of study treatment.

11. Known potassium, sodium, calcium abnormalities, or hypoalbuminemia, interstitial lung disease, non-infectious pneumonia, or other uncontrolled systemic diseases, including diabetes, hypertension, cardiovascular diseases (e.g., active cardiac disease within 6 months before enrollment, including severe/unstable angina, myocardial infarction, symptomatic congestive heart failure, and requiring medication for ventricular arrhythmias).

12. Untreated chronic hepatitis B patients with HBV DNA ≥500 IU/mL (2500 copies/mL) or HBV carriers are not eligible. Note: Patients with inactive hepatitis B surface antigen carriers or stable active HBV infection (HBV DNA <500 IU/mL [2500 copies/mL]) after continuous antiviral treatment can be enrolled. HBV DNA testing is performed only in patients positive for antibodies to the hepatitis B core antigen.

13. Patients with active hepatitis C are not eligible. Patients who test negative for HCV antibodies during the screening period or, if positive, test negative for HCV RNA after positive HCV antibody testing can be enrolled. Only patients positive for HCV antibodies need HCV RNA testing.

14. History of immune deficiency (including human immunodeficiency virus [HIV] positive, other acquired, congenital immunodeficiency diseases) or a history of allogeneic stem cell transplantation or organ transplantation.

15. Known allergies to other monoclonal antibodies.

16. Known allergies to any study drug or excipient.

17. Patients with toxic side effects (due to any treatment) that have not returned to baseline or a stable level, unless the investigator does not believe that such toxic side effects may pose a safety risk (e.g., hair loss, neurologic symptoms, and specific laboratory abnormalities).

18. Underlying medical conditions, alcohol/drug abuse, or dependence that may adversely affect the administration of study drug, interpretation of results, or lead to a high risk of treatment complications.

19. Concurrent participation in another therapeutic clinical study.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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210 participants in 2 patient groups

Arm 1

Active Comparator group

Description:

During each 21 days study cycle(up to 6 cycles), all participants will receive: Tislelizumab: Taken 1x time at d1 each cycle or until it is determined participant must stop the drug. Gemcitabine: d1, d8 each cycle or until it is determined participant must stop the drug. Cisplatin: d2 each cycle or until it is determined participant must stop the drug. Tislelizumab maintenance therapy:after chemoimmunotherapy, q3W until it is determined participant must stop the drug, or 2 years of treatment is completed.

Treatment:

Drug: Tislelizumab, Cisplatin, Gemcitabine

Arm 2

Experimental group

Description:

During each 21 days study cycle(up to 6 cycles), all participants will receive: Tislelizumab: Taken 1x time at d1 each cycle or until it is determined participant must stop the drug. Gemcitabine: d1, d8 each cycle or until it is determined participant must stop the drug. Cisplatin: d2 each cycle or until it is determined participant must stop the drug. Trilaciclib: d1, d2, d8 each cycle or until it is determined participant must stop the drug. Tislelizumab maintenance therapy:after chemoimmunotherapy, q3W until it is determined participant must stop the drug, or 2 years of treatment is completed.

Treatment:

Drug: Tislelizumab, Cisplatin, Gemcitabine and Trilaciclib