RC48 Combined With Tislelizumab for Bladder Sparing Treatment in NMIBC With BCG Treatment Failure and HER2 Expression

Inclusion Criteria:

1. ≥18 years old
2. Histologically confirmed recurrent, non-muscle invasive bladder cancer;
3. Histopathology: Patients with any variant urothelial cell carcinoma (UCC) (i.e.,squamous and/or glandular epithelial differentiation UCC, UCC with micropapillarychanges, nest variant UCC, plasmacytoid UCC, neuroendocrine UCC, and sarcomatoidUCC) were enrolled. The presence of any lymphatic infiltration (LVI) isconsidered evidence of high risk.
4. Papillary carcinoma must be a high-risk disease defined as a high grade Ta/T1lesion. In addition, subjects must have all visible tumors completely removedprior to initial administration of the study drug, as documented at baselinecystoscopy. Cytological results for high-grade urothelial carcinoma must benegative prior to initial administration of the investigational drug.
5. CIS does not require complete excision, but must be completely excised withcoexisting papillary carcinoma prior to enrollment and documented at baselinecystoscopy. Negative urine cytology for malignant cells is not required.
6. When BCG recurred after treatment, the presence of HER2 expression was detected by IHCin the pathology department of our hospital
7. BCG treatment failure included no response to BCG treatment and relapse afterinadequate BCG treatment
8. Subjects without response after adequate BCG treatment must meet at least one ofthe following criteria: 1) Persistent or recurrent simple CIS with or withoutrecurrent Ta/T1 (non-invasive papillary carcinoma/tumor invasion of subepithelialconnective tissue) disease within 12 months after completion of adequate BCGtreatment; 2) Recurrent high-grade Ta/T1 disease occurred within 6 months aftercompletion of adequate BCG treatment; 3) T1 high-grade disease was present at thefirst disease assessment after completion of a BCG induction course. Adequate BCGtreatment (minimum treatment requirement) : at least 5 out of 6 full dosetreatments were received during the initial induction course and at least 1maintenance treatment within 6 months (one full dose per week and 2 out of 3completed treatments); Or received at least 5 out of 6 full doses in the initialinduction course and at least 2 out of 6 full doses in the second inductioncourse.
9. Relapse after inadequate BCG treatment: Subjects must meet the followingcriteria: Recurrence of high-grade Ta/T1 disease within 12 months of completionof BCG treatment (as defined below): Previous inadequate BCG treatment (minimumtreatment requirement) included receiving at least 5 out of 6 full dosetreatments during the initial induction course. Or received at least 5 out of 6full dose treatments during the initial induction course and at least 1maintenance treatment (once a week and 2 out of 3 completed treatments) within 6months. One half or one third of the dose is allowed during maintenancetreatment.
10. To refuse or be unsuitable for radical cystectomy
11. ECOG 0~1
12. The major organs are functioning normally, the following criteria are met:

(1) The blood routine examination criteria should meet (no blood transfusion and notreatment with granulocyte colony stimulating factor within 14 days before enrollment) : i.Absolute count of neutrophils (ANC) ≥1,000/mm3 ii. Platelet count ≥75,000/mm3 iii.Hemoglobin ≥ 8.0g /dL (2) Liver function: i. Total bilirubin ≤1.5× prescribed ULN or directbilirubin ≤ULN for subjects with total bilirubin levels >1.5×ULN ii. Upper limit of normalvalues (ULN) ≤2.5 times of alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) Note: ≤1.5× ULN (This criterion only applies to patients who have not receivedanticoagulant therapy; Patients receiving anticoagulant therapy should keep anticoagulantswithin therapeutic limits); (3) Kidney function: The Cockcroft-Gault formula was used todetermine the creatinine clearance (CrCl) > 30 mL/min. 8. Subjects (or their legal representatives) must sign an informed consent form (ICF)indicating that they understand the purpose and procedures of the study and are willing toparticipate in the study; 9. Fertile women must have a negative pregnancy test result (beta-hCG) (urine or serum) within 7 days before the study drug is first administered.

Exclusion Criteria:

1. Confirmed by histology of muscular layer infiltration (T2 or higher level) bladderurothelial carcinoma.
2. Histopathological examination revealed any bladder small cell composition, pure, puresquamous cell carcinoma or simple squamous adenocarcinoma CIS;
3. Received other PD - 1 / PD - L1 inhibitor and/or HER2 inhibitor;
4. Active malignancies other than the disease being treated (i.e., disease progressionwithin the last 24 months or requiring a change in treatment). Only the followingspecial circumstances are allowed: i. Skin cancer that has been treated and completelycured within the last 24 months; ii. Adequately treated lobular carcinoma in situ (LCIS) and ductal CIS; iii. A history of local breast cancer and receivingantihormonal drugs or a history of local prostate cancer (N0M0) and receiving androgenblocking therapy.
5. History of uncontrolled cardiovascular disease, including: 1) any of the following inthe past 3 months: unstable angina, myocardial infarction, ventricular fibrillation,toroidal ventricular tachycardia, cardiac arrest, or known congestive New York HeartAssociation Class III-IV heart failure, cerebrovascular accident, or transientischemic attack; 2) Prolonged QTc interval confirmed by ECG evaluation duringscreening (Fridericia; QTc > 480 ms); 3) Pulmonary embolism or other venousthromboembolism within the past 2 months.
6. Pregnancy or lactation women;
7. Known human immunodeficiency virus (HIV) infection, unless the subjects in the pastsix months or longer had accepted the stability of antiretroviral therapy (art), andno opportunistic infections occurred in the past 6 months, and over the past sixmonths the CD4 count of > 350;
8. Have evidence of active hepatitis B or hepatitis C infection (for example, a historyof hepatitis C but hepatitis C virus polymerase chain reaction detection results andnormal subjects of hepatitis B surface antigen antibody positive hepatitis B cangroups);
9. Has yet to recover from past the toxic effects of anticancer therapy (except noclinical significance of toxic effects, such as hair loss, skin discoloration,neuropathy, and hearing impairment).
10. Wound healing delay, defined as the skin/decubitus ulcer, chronic leg ulcer, had knowngastric ulcer or incision to heal.
11. 1 cycle day 1 major surgery within 4 weeks before (don't think TURBT belong to majorsurgery).
12. Other patients assessed by the investigator as unsuitable for participation in thestudy.