Combination treatment for bladder cancer patients who can't undergo surgery

RC48 Combined With Tislelizumab for Bladder Sparing Treatment in High-risk Non-muscular Invasive Bladder Cancer (NMIBC) With BCG Treatment Failure and HER2 Expression

This study is testing a new combination treatment for bladder cancer in patients who can't have surgery and have not responded to previous therapy, to see if it can help them without removing their bladder.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: RenJi Hospital (Academic / other)
• Drugs / interventions: Tislelizumab, Toripalimab, chemotherapy, Immunotherapy
• Locations: 1 site (Shanghai, Shanghai Municipality)
• Trial ID: NCT05957757 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the efficacy and safety of a combination therapy using RC48 and Tislelizumab for patients with non-muscle invasive bladder cancer (NMIBC) who have failed prior BCG treatment and refuse or are unsuitable for radical cystectomy. The study involves approximately 20 participants who will receive the treatment over two years, following a thorough assessment including Transurethral resection of bladder tumor (TURBT) and biological sample collection. The aim is to provide a bladder-sparing option for high-risk patients expressing HER2, addressing the need for alternative therapies in this population.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with recurrent, high-risk NMIBC expressing HER2 who have failed BCG treatment and are unwilling or unsuitable for cystectomy.

Not a fit: Patients with muscle-invasive bladder cancer or those who are not HER2 positive may not benefit from this treatment.

Why it matters

Potential benefit: If successful, this treatment could offer a viable bladder-sparing option for patients with high-risk NMIBC, potentially improving their quality of life and reducing the need for invasive surgery.

How similar studies have performed: While there have been studies exploring immunotherapy for bladder cancer, this specific combination approach is novel and has not been extensively tested.

Eligibility criteria

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.

Where this trial is running

Shanghai, Shanghai Municipality

• Ethics Committee of Shanghai Renji Hospital — Shanghai, Shanghai Municipality, China (Recruiting)

Study contacts

• Study coordinator: Wei Xue, Doctor

Conditions Non-Muscle Invasive Bladder Cancer; HER2; HER2 expression; BCG Failure; Unsuitable or refused to radical cystectomy