Brief Title: A Study to Evaluate the Safety and Efficacy of Oral APL-1202 in Combination With Tislelizumab Compared to Tislelizumab Alone as Neoadjuvant Therapy in Patients With Muscle Invasive Bladder Cancer

PRIMARY OUTCOMES

Primary Outcome 1 - Measure:

Primary Outcome 1 - Timeframe: N/A

CONDITION

• Muscle Invasive Bladder Cancer

ELIGIBILITY

Inclusion Criteria:
1. Willing and able to provide written informed consent.

- 2. Age ≥ 18 years.

- 3. Histopathologically confirmed transitional cell carcinoma of the bladder. Patients with mixed histologies are required to have a dominant (i.e. > 50%) transitional cell pattern.

- 4. Radical cystectomy is planned (according to local guidelines).

- 5. Patients who refuse neoadjuvant cisplatin based chemotherapy or in whom neoadjuvant cisplatin based therapy is contraindicated. Contraindications to cisplatin is defined by meeting at least one of the following criteria:
* Impaired renal function with calculated CrCl 30 to 59 mL/min (by Cockcroft-Gault equation).

- * Eastern Cooperative Oncology Group (ECOG) Performance Status 2.

- * CTCAE v.5 Grade ≥2 audiometric hearing loss.

- * In the clinical judgement of the investigator, potential adverse effects from cisplatin-based neoadjuvant chemotherapy outweighs its benefits.

- 6. Clinical stage T2-T4a N0 M0 disease by CT (or MRI) (within 4 weeks of randomization).

- 7. Residual disease after transurethral resection of bladder (TURB) (surgical opinion, cystoscopy or radiological presence).

- 8. Availability of representative formalin-fixed paraffin-embedded (FFPE) tumor specimens or unstained slides, with an associated pathology report, and determined to be evaluable for tumor PD-L1 expression prior to study enrollment;

- 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.

- 10. Adequate hematologic and end-organ functions:
* Hemoglobin > 9.0 g/dL;

- * Absolute neutrophil count (ANC) > 1.5×109 /L;

- * Platelet count > 100×109 /L;

- * Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).

- * Aspartate aminotransferase (AST) /alanine aminotransferase (ALT) ≤ 2.5 x institutional upper limit of normal ULN.

- * CrCl (calculated using Cockcroft-Gault equation) ≥ 30 mL/min (calculated CrCl ≥ 50 mL/min in Phase Ⅰ: Dose-Escalation).

- * INR < 1.5. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. - 11. Female patients should be surgically sterilized or post-menopausal or must agree to take effective contraceptive measures during the treatment. Male patients must be surgically sterilized or must agree to take effective contraceptive measures during treatment. Patients must continue to take contraceptive measures for 3 months after the investigational therapy was completed.
Exclusion Criteria:
1. Previous systemic therapy for bladder cancer.

- 2. Malignancies other than urothelial bladder cancer within 5 years prior to cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ of breast treated surgically with curative intent).

- 3. Evidence of measurable nodal or metastatic disease.

- 4. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome).

- 5. Pregnant female patients. All female patients with a positive pregnancy test within 2 weeks prior to the first dose of study treatment will be excluded from the study.

- 6. Significant cardiovascular disease, such as New York Heart Association cardiac disease (more than Class II), myocardial infarction within 3 months prior to enrollment, unstable arrhythmias, or unstable angina.

- 7. Severe infections within 4 weeks prior to enrollment in the study including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.

- 8. Major surgical procedure within 4 weeks prior to enrollment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis.

- 9. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.

- 10. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the tislelizumab or APL-1202 formulation.

- 11. History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

- 12. History of autoimmune-related hypothyroidism, unless on a stable dose of thyroid-replacement hormone.

- 13. History of idiopathic pulmonary fibrosis.

- 14. Uncontrolled Type 1 diabetes mellitus.

- 15. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.

- 16. Prior allogeneic stem cell or solid organ transplantation.

- 17. Positive test for HIV.

- 18. Uncontrolled hepatitis infection.

- 19. Active tuberculosis.

- 20. Optic nerve disorders or with a history of optic nerve disorders.

- 21. Cataract or with a history of cataract.

- 22. Prior treatment with anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents.

- 23. Patients taking regular oral steroids, above the allowed limit of 10 mg/day methylprednisolone/prednisone or analogues, for any reason. Patients must not have had steroids for 4 weeks prior to study entry.

- 24. Administration of vaccine within 4 weeks prior to enrollment or anticipation that such a vaccine will be required during the study.

- 25. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrollment.

- 26. Treatment with systemic immunostimulatory agents within 4 weeks prior to enrollment.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: N/A

Role: N/A

Affiliation: N/A

Overall Contact

Name: Mingming Zhang, MD

Phone: +8613816002336

Email: mmzhang@asieris.cn

LOCATION