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

Overview

This is a prospective, open, single-center clinical study of anti-HER2-ADC combined with PD-1 monoclonal antibody for bladder sparing treatment in non-muscular invasive bladder cancer (NMIBC) patients with HER2-expressing. The study was conducted in accordance with the Good Clinical Practice (GCP). Approximately 20 subjects will be enrolled to evaluate the efficacy and safety of RC48 (RC48 2.0 mg/kg intravenously administered every two weeks) combined with Tislelizumab (Tislelizumab 200 mg intravenously administered every three weeks).

Subjects undergo Transurethral resection of bladder tumor (TURBT), imaging diagnosis and pre-treatment biological samples of blood, urine and biopsy tissue.

The study will include high-risk NMIBC patients who express HER2, fail after BCG treatment, but refuse to undergo cystectomy or do not meet the requirements for cystectomy.

Subjects will receive RC48 and Tislelizumab for two years. BI-DFS were evaluated by cystoscopy, histopathologic examination, laboratory examination, and imaging examination after treatment, and tumor efficacy was evaluated when clinical studies reached the number of subjects specified in the protocol for efficacy evaluation.

Description

For Non-muscle invasive bladder cancer (NMIBC), Transurethral resection of bladder tumor (TURBT) is the primary treatment. TURBT relapses within 12 months after surgery in 10% to 67% of patients, and postoperative bladder perfusion therapy (including chemotherapy and Immunotherapy) significantly reduces the recurrence rate. However, about 30%-40% of patients will relapse after BCG treatment. Radical cystectomy is the standard of care for patients who do not respond to BCG treatment and have high grade NMIBC. However, radical cystectomy has a high incidence of postoperative complications (up to 60%) and a negative impact on HRQoL. These complications occur even in high-volume centers of excellence, whether open or minimally invasive, and the mortality rate from the surgery itself is about 3%. Therefore, some patients refuse to undergo radical cystectomy. In addition, some patients are medically unfit for surgery due to age, functional status, American Society of Anesthesiologists classification, comorbiditions, body mass index, and other factors. Although penerubicin is the only bladder sparing drug approved by the U.S. Food and Drug Administration (FDA) for patients who are not suitable for or unwilling to undergo cystectomy, BCG refractory, and with CIS NMIBC, no legally marketed penerubicin drug is available in China. Therefore, new treatments are needed to prevent invasive bladder cancer from affecting the entire bladder.

In recent years, immunocheckpoint inhibitors represented by PD-1/PD-L1 have been proved to be a promising means of tumor immunotherapy, which has made a breakthrough in the treatment of advanced urothelial carcinoma, and become the main choice for the treatment of advanced urothelial carcinoma. Immunocheckpoint inhibitors also showed positive results in patients who did not respond to BCG treatment during perioperative and perioperative periods.Therefore, immunotherapy is expected to be an alternative bladder sparing therapy for high-risk NMIBC patients.The anti-HER2-ADC drug RC48 also achieved significant efficacy in HER2-overexpressed advanced urothelial carcinoma, and its combination with PD-1 monoclonal antibody Toripalimab was more effective in the first-line treatment of advanced metastatic urothelial carcinoma. Therefore, RC48 combined with PD-1 can be used as a potential treatment for bladder sparing in patients with NMIBC.

In NMIBC patients with HER2 expression, ADC drugs can target tumor cells and deliver cytotoxic drugs with greater safety than chemotherapy. In addition, the application of anti-HER2-ADC drugs combined with PD-1 in bladder sparing therapy is still lacking in experience and related studies. Therefore, we plan to conduct a study on bladder preservation therapy for patients with HER2-expressing NMIBC treated with ADC drugs combined with PD-1 monoclonal antibody, so as to preserve the bladder function of patients while controlling tumor recurrence and ensuring their quality of life.

Eligibility

Inclusion Criteria:

1. ≥18 years old
2. Histologically confirmed recurrent, non-muscle invasive bladder cancer;
   1. Histopathology: Patients with any variant urothelial cell carcinoma (UCC) (i.e., squamous and/or glandular epithelial differentiation UCC, UCC with micropapillary changes, nest variant UCC, plasmacytoid UCC, neuroendocrine UCC, and sarcomatoid UCC) were enrolled. The presence of any lymphatic infiltration (LVI) is considered evidence of high risk.
   2. Papillary carcinoma must be a high-risk disease defined as a high grade Ta/T1 lesion. In addition, subjects must have all visible tumors completely removed prior to initial administration of the study drug, as documented at baseline cystoscopy. Cytological results for high-grade urothelial carcinoma must be negative prior to initial administration of the investigational drug.
   3. CIS does not require complete excision, but must be completely excised with coexisting papillary carcinoma prior to enrollment and documented at baseline cystoscopy. Negative urine cytology for malignant cells is not required.
3. When BCG recurred after treatment, the presence of HER2 expression was detected by IHC

   in the pathology department of our hospital

4. BCG treatment failure included no response to BCG treatment and relapse after inadequate BCG treatment
   1. Subjects without response after adequate BCG treatment must meet at least one of the following criteria: 1) Persistent or recurrent simple CIS with or without recurrent Ta/T1 (non-invasive papillary carcinoma/tumor invasion of subepithelial connective tissue) disease within 12 months after completion of adequate BCG treatment; 2) Recurrent high-grade Ta/T1 disease occurred within 6 months after completion of adequate BCG treatment; 3) T1 high-grade disease was present at the first disease assessment after completion of a BCG induction course. Adequate BCG treatment (minimum treatment requirement) : at least 5 out of 6 full dose treatments were received during the initial induction course and at least 1 maintenance treatment within 6 months (one full dose per week and 2 out of 3 completed treatments); Or received at least 5 out of 6 full doses in the initial induction course and at least 2 out of 6 full doses in the second induction course.
   2. Relapse after inadequate BCG treatment: Subjects must meet the following criteria: Recurrence of high-grade Ta/T1 disease within 12 months of completion of BCG treatment (as defined below): Previous inadequate BCG treatment (minimum treatment requirement) included receiving at least 5 out of 6 full dose treatments during the initial induction course. Or received at least 5 out of 6 full dose treatments during the initial induction course and at least 1 maintenance treatment (once a week and 2 out of 3 completed treatments) within 6 months. One half or one third of the dose is allowed during maintenance treatment.
5. To refuse or be unsuitable for radical cystectomy
6. ECOG 0~1
7. The major organs are functioning normally, the following criteria are met:

        (1) The blood routine examination criteria should meet (no blood transfusion and no
        treatment 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 direct
        bilirubin ≤ULN for subjects with total bilirubin levels >1.5×ULN ii. Upper limit of normal
        values (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 received
        anticoagulant therapy; Patients receiving anticoagulant therapy should keep anticoagulants
        within therapeutic limits); (3) Kidney function: The Cockcroft-Gault formula was used to
        determine 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 to
        participate 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) bladder
             urothelial carcinoma.
          2. Histopathological examination revealed any bladder small cell composition, pure, pure
             squamous 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 progression
             within the last 24 months or requiring a change in treatment). Only the following
             special circumstances are allowed: i. Skin cancer that has been treated and completely
             cured within the last 24 months; ii. Adequately treated lobular carcinoma in situ
             (LCIS) and ductal CIS; iii. A history of local breast cancer and receiving
             antihormonal drugs or a history of local prostate cancer (N0M0) and receiving androgen
             blocking therapy.
          5. History of uncontrolled cardiovascular disease, including: 1) any of the following in
             the past 3 months: unstable angina, myocardial infarction, ventricular fibrillation,
             toroidal ventricular tachycardia, cardiac arrest, or known congestive New York Heart
             Association Class III-IV heart failure, cerebrovascular accident, or transient
             ischemic attack; 2) Prolonged QTc interval confirmed by ECG evaluation during
             screening (Fridericia; QTc > 480 ms); 3) Pulmonary embolism or other venous
             thromboembolism within the past 2 months.
          6. Pregnancy or lactation women;
          7. Known human immunodeficiency virus (HIV) infection, unless the subjects in the past
             six months or longer had accepted the stability of antiretroviral therapy (art), and
             no opportunistic infections occurred in the past 6 months, and over the past six
             months the CD4 count of > 350;
          8. Have evidence of active hepatitis B or hepatitis C infection (for example, a history
             of hepatitis C but hepatitis C virus polymerase chain reaction detection results and
             normal subjects of hepatitis B surface antigen antibody positive hepatitis B can
             groups);
          9. Has yet to recover from past the toxic effects of anticancer therapy (except no
             clinical 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 known
             gastric ulcer or incision to heal.
         11. 1 cycle day 1 major surgery within 4 weeks before (don't think TURBT belong to major
             surgery).
         12. Other patients assessed by the investigator as unsuitable for participation in the
             study.