Disitamab Vedotin Combined With Tislelizumab for Her2 Overexpressing High-Risk Non-Muscle-Invasive Urothelial Bladder Carcinoma Which is Not Completely Resectable

Study Overview
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Brief Summary
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This is a phase II study to determine the safety and efficacy of Disitamab Vedotin when given in combination with Tislelizumab as treatment for patients with Her2 overexpressing high-risk non-muscle-invasive bladder cancer (HR NMIBC) which is not completely resectable. Patients will receive treatment with Disitamab Vedotin in combination with tislelizumab every 3 weeks for 4 treatment cycles over 12 weeks followed by transurethral resection biopsy.

Official Title
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An Open Label, Phase 2 Study of Disitamab Vedotin Combined With Tislelizumab for Patients With Her2 Overexpressing (IHC2+ or 3+) High-Risk Non-Muscle-Invasive Urothelial Bladder Carcinoma Which is Not Completely Resectable

Conditions
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Her2 Overexpressing High-Risk Non-Muscle Invasive Bladder Urothelial Carcinoma

Intervention / Treatment
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* Drug: Disitamab Vedotin Tislelizumab
* Drug: Disitamab Vedotin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years; Urothelial carcinoma with Her2 IHC 2+ or 3+; High-risk non-muscle-invasive urothelial carcinoma or high-risk non-muscle-invasive urothelial carcinoma as the main pathological component > 50%, difined as following: a. T1 b. High-grade Ta c.Carcinoma in situ(CIS); Multi-point biopsy of bladder shows there are more than 2 section and over 3 points of pathological specimens are diagnosed as above, meanwhile, the tumor has to be diagnosed as not completely resectable by at least 2 senior urologist; Agreed to provide tissue examination samples (for detection of PD-L1 expression, tumor mutation load, IHC, detection of DNA and RNA, etc;) Organ function level must meet or under the support treatment meet the following requirements: Hematological indexes: neutrophil count >= 1.5x10^9/L, platelet count >= 100x10^9/L, hemoglobin >= 9.0 g/dl; Liver function: total bilirubin <=1.5 ULN, alanine aminotransferase and aspartate aminotransferase <=2.5 ULN（patient with metastatic liver cancer：aminotransferase <=5.0 ULN）; Renal function: creatinine ≤ 1.5 times the upper limit of normal, and creatinine clearance ≥ 50 ml/min; The subjects volunteered to join the study, signed informed consent, and had good compliance with follow-up; Exclusion Criteria: Active, known or suspected autoimmune diseases; History of primary immunodeficiency; Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation; Pregnant or lactating female patients; Untreated acute or chronic active hepatitis B or hepatitis C infection. Under the condition of monitoring the virus copy number of patients receiving antiviral treatment, doctors can judge whether they are in line with the patients' individual conditions; Prior use of immunosuppressive drugs within 4 weeks prior to the start of treatment, excluding nasal and inhaled corticosteroids or physiological doses of systemic steroids (i.e. not more than 10 mg / day prednisolone or other corticosteroids with the same physiological dose); Known or suspected allergy to disitamab vedotin or tislelizumab; Have a clear history of active tuberculosis; Participating in other clinical researchers; Men with reproductive capacity or women who are likely to become pregnant do not take reliable contraceptive measures; Uncontrolled concurrent diseases, including but not limited to: HIV infected (HIV antibody positive); Severe infection in active stage or poorly controlled; Evidence of serious or uncontrollable systemic diseases (such as severe mental, neurological, epilepsy or dementia, unstable or uncompensated respiratory, cardiovascular, liver or kidney diseases, uncontrolled hypertension [i.e. hypertension greater than or equal to CTCAE grade 2 after drug treatment]); Patients with active bleeding or new thrombotic disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Disitamab Vedotin and Tislelizumab<br>Disitamab Vedotin 120mg IV on day 1 in combination with Tislelizumab 200mg IV on day 2 every 3 weeks for 3 or 4 cycles followed by transurethral resection biopsy. | Drug: Disitamab Vedotin Tislelizumab<br>* Disitamab Vedotin 120mg will be administered on Day 1 of each cycle for 4 treatment cycles;Tislelizumab 200mg will be administered on Day 2 of each cycle for 4 treatment cycles.<br>* Other names: KEYNOTE-057;|
| Other: Disitamab Vedotin<br>Disitamab Vedotin 120mg IV on day 1 every 3 weeks for 3 or 4 cycles followed by transurethral resection biopsy. | Drug: Disitamab Vedotin<br>* Disitamab Vedotin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate |  | At the time of transurethral resection biopsy (within 9 or 12 weeks of the first dose of disitamab vedotin) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progress Free Survival（PFS） |  | up to 3 years | 
| Recurrence Free Survival（RFS） |  | up to 3 years | 
| Cystectomy-Free Survival (CFS) | defined from D1 of treatment until cystectomy | up to 3 years | 
| Duration of Response (DOR) |  | up to 3 years | 
| Event-Free Survival（EFS） | defined from D1 of treatment until the time of any events，included progressive disease，discontinue treatment for any cause or death | up to 3 years | 
| Number of adverse events and severity by grade (CTCAE) | Safety and toxicity will be characterized according to the reported adverse event (AE) profile using NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0, as well as a patient questionnaire derived from the Patient Reported Outcomes (PRO)-CTCAE and Patient Reported Outcomes Measurement Information System (PROMIS). | 12 weeks of treatment plus 30 days for toxicity followup | 
| Her2 status |  | up to 3 years | 
| PD-1 expression status |  | up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Disitamab Vedotin, Tislelizumab