Neoadjuvant Toripalimab in Combination with Gemcitabine and Cisplatin Therapy in Local Advanced Bladder Cancer Subjects

Phase II Study of Neoadjuvant Toripalimab with Gemcitabine-Cisplatin in Subjects with T2-4aN0M0 Bladder Cancer: GZZJU-2021NB

This is a pre-surgical study involving subjects with local advanced bladder cancer, who are candidates for neoadjuvant therapy. It is a single-arm phase II portion.

Outline: This study is a single-arm, open, exploratory clinical trial;

Subjects receive: gemcitabine 1000mg/m2 IV Day1 and Day8 every 21 days repeated for 4 cycles; cisplatin 35mg/m2 IV Day1 and Day2 every 21 days, repeated for 4 cycles.

Toripalimab at recommended phase II dose is given every 3 weeks for 4 doses starting with Cycle1 Day1(C1D1).

Subjects will then have surgery to remove their primary tumor within 6 weeks after their last dose of neoadjuvant therapy.

Eastern Cooperative Oncology Group (ECOG) performance status: 0-1

Demonstrate adequate organ function as defined by the following laboratory values at study entry. All screening labs should be performed within 28 days of C1D1.

Hematopoetic:

Absolute neutrophil count (ANC) ≥1,500 /mcL Absolute lymphocyte count ≥350 mcL Platelets ≥100,000 / mcL Hemoglobin ≥9 g/dL or ≥5.6 mmol/L

Renal: Measured or calculated creatinine clearance ≥30 mL/min

Hepatic:

Serum total bilirubin ≤ 1.25 X ULN OR ≤ 2.5 x ULN for subjects with Gilbert's disease Aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) ≤ 2 X ULN

Coagulation:

International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy and as long as PT or PTT is within therapeutic range of intended use of anticoagulants

Inclusion Criteria:

• Patients between 18 and 75 years old on day of signing informed consent, regardless of gender;
• ECOG score 0-1 points, expected survival time> 6 months;
• Pathologically confirmed locally advanced bladder urothelial carcinoma (cT2-T4a, N≤1, M0, tumor staging according to American Joint Committee on Cancer (AJCC), 2017, eighth edition);
• Appropriate and plan for radical cystectomy;
• According to the RECIST1.1 standard, there is at least one measurable lesion (spiral CT scan ≥10mm);
• Since the diagnosis of locally advanced bladder urothelial carcinoma, patient has not received anti-tumor system treatment;
• The main organ functions are normal, and the following requirements must be met within 2 weeks before the first study treatment:
• Routine blood examination must meet: WBC≥4.0×109/L; PLT≥90×109/L; Hb≥90g/L (patients can be infused with red blood cells to meet this standard);
• Blood biochemical examination must meet: serum creatinine (Cr) ≤1.5 times the upper limit of normal (ULN) or endogenous creatinine clearance ≥60mL/min; TBIL≤1.5×ULN; ALB≥30g/L; ALT and AST≤ 3.0×ULN; TSH≤1.5×ULN.
• Female patients with fertility must undergo a pregnancy test (serum or urine) within 7 days before enrollment, and the result is negative, and they voluntarily adopt appropriate methods of contraception during the observation period and within 8 weeks after the last administration;
• Agree to provide diagnosis and treatment-related tumor tissue specimens for clinical research, and have the ability to follow the planned research visit until the clinical recurrence/progress is clear.
• Sign informed consent voluntarily.

Exclusion Criteria:

• Have previously received anti-PD1/PDL1/CTLA-4 antibody treatment or systemic chemotherapy, bladder infusion chemotherapy is excluded;
• Have received bladder bacille Calmette Guerin (BCG) infusion therapy within 4 weeks;
• Have received radiotherapy of the bladder in the past;
• Patients with any history of active autoimmune disease or autoimmune disease;
• Complicated diseases that require the use of immunosuppressive drugs; concurrent diseases that require the use of immunosuppressive agents for systemic or locally absorbable corticosteroids. It is forbidden to use prednisone greater than 10 mg/day or the same dose in the 2 weeks before the use of the study drug;
• Combined with other malignant tumors;
• Have a history of allergy to other antibody drugs;
• The history of human immunodeficiency virus (HIV) infection;
• The subject has active infection, including active tuberculosis;
• Combined with severe heart disease, or combined with New York Heart Association (NYHA) grade 3 or 4 cardiac insufficiency;
• Kidney transplant patients;