Muscle-Invasive Bladder Cancer (MIBC)
Conditions
Keywords
HER2-Expressing Bladder Cancer, Bladder Preservation, Trastuzumab Rezetecan, Adebrelimab, Concurrent Radiotherapy, Response-Guided Treatment
Brief summary
This prospective, multicenter, open-label phase II study will evaluate a response-guided bladder-preservation strategy in patients with HER2-expressing muscle-invasive bladder cancer. Participants will receive maximal transurethral resection of the bladder tumor, trastuzumab rezetecan plus adebrelimab, and concurrent bladder radiotherapy. Treatment response will be assessed by cystoscopic biopsy or diagnostic transurethral resection at 8 weeks (±2 weeks) after radiotherapy. Participants with a pathological stage of T1 or lower may continue bladder-preserving management, whereas radical cystectomy will be recommended for participants with disease above T1. The primary outcome is the major pathological response rate.
Detailed description
This is a prospective, multicenter, open-label, single-arm phase II study designed to evaluate the efficacy and safety of a response-guided bladder-preserving strategy using trastuzumab rezetecan plus adebrelimab in combination with bladder radiotherapy in patients with HER2-expressing muscle-invasive bladder cancer (MIBC). Approximately 70 participants with clinically staged cT2-T4a, N0, M0 MIBC will be enrolled. Eligible participants will undergo maximal transurethral resection of the bladder tumor (TURBT), followed by trastuzumab rezetecan at 4.8 mg/kg intravenously every 3 weeks for 4 cycles and adebrelimab at 1200 mg intravenously every 3 weeks for 4 cycles. Bladder radiotherapy will be initiated concurrently with systemic therapy and delivered to a total dose of 60-64 Gy in 30-32 fractions, at 2.0 Gy per fraction, once daily, 5 fractions per week, over approximately 6 weeks. At 8 weeks (±2 weeks) after completion of radiotherapy, participants will undergo cystoscopic biopsy or diagnostic TURBT to assess pathological response. Participants with a pathological stage of T1 or lower (ypT0, ypTa, ypTis, or ypT1) may continue bladder-preserving management with close surveillance. Radical cystectomy will be recommended for participants with residual disease above pathological stage T1. The primary outcome is the major pathological response rate, defined as the proportion of participants with a pathological stage of T1 or lower at post-radiotherapy assessment. Secondary outcomes include event-free survival, overall survival, bladder preservation rate, 1-year and 2-year bladder event-free survival, and safety and tolerability.
Interventions
Trastuzumab rezetecan will be administered intravenously at a dose of 4.8 mg/kg every 3 weeks for 4 cycles.
DRUGAdebrelimab
Adebrelimab will be administered intravenously at a dose of 1200 mg every 3 weeks for 4 cycles.
RADIATIONConcurrent Bladder Radiotherapy
Bladder radiotherapy will be delivered to a total dose of 60-64 Gy in 30-32 fractions, at 2.0 Gy per fraction, once daily, 5 fractions per week, over approximately 6 weeks. Radiotherapy will be initiated concurrently with systemic therapy.
Participants will undergo maximal transurethral resection of the bladder tumor before combined treatment. Cystoscopic biopsy or diagnostic TURBT will be performed at 8 weeks (±2 weeks) after radiotherapy to assess pathological response.
Sponsors
Tongji Hospital
Jiangsu Hengrui Pharmaceutical Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion Criteria: 1. Age ≥18 years, male or female; able to provide written informed consent; willing and able to comply with all protocol-required examinations and follow-up. 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 3. Histologically confirmed muscle-invasive urothelial carcinoma of the bladder. Minor squamous, glandular, or other mixed differentiation is permitted. Patients with pure non-urothelial carcinoma may be enrolled at the investigator's discretion. 4. Clinical stage cT2-T4a, N0, M0, based on pelvic/abdominal imaging with or without chest imaging. 5. HER2 expression of IHC 1+, 2+, or 3+ in tumor tissue, as determined by a central or designated laboratory. 6. Suitable for maximal transurethral resection of the bladder tumor (TURBT) and considered by a multidisciplinary team to be eligible for radical cystectomy if required. 7. Adequate organ function: absolute neutrophil count ≥1.5 × 10\^9/L; platelet count ≥100 × 10\^9/L; hemoglobin ≥90 g/L; ALT and AST ≤2.5 × upper limit of normal (ULN); total bilirubin ≤1.5 × ULN; eGFR ≥50 mL/min/1.73 m² or CrCl ≥50 mL/min; INR ≤1.5 × ULN if not receiving anticoagulant therapy; left ventricular ejection fraction ≥50% or the institutional lower limit of normal; and no uncontrolled clinically significant cardiovascular disease. 8. No active interstitial lung disease or pneumonitis on baseline pulmonary assessment, including chest CT. 9. Participants of childbearing potential must agree to use effective contraception during the study and for the protocol-specified period after the last dose. A negative pregnancy test is required when applicable.
Exclusion criteria
* 1\. Distant metastasis (M1), clearly uncontrollable extra-regional metastatic disease, or an upper urinary tract tumor requiring priority treatment. 2\. Previous systemic anticancer treatment for the current bladder cancer, including chemotherapy, immunotherapy, anti-HER2 targeted therapy, or antibody-drug conjugates, or previous pelvic radiotherapy that could affect the delivery or safety of study radiotherapy. 3\. Unable to complete protocol-required local treatment, including inability to undergo maximal TURBT or the presence of a contraindication to radiotherapy, such as previous high-dose irradiation to the same region or active inflammatory bowel disease. 4\. Active autoimmune disease or a history requiring long-term systemic immunosuppressive treatment, including prednisone ≥10 mg/day or equivalent within 14 days before treatment. Physiologic replacement doses are permitted. 5\. Active pneumonitis or interstitial lung disease, or a history of severe drug-related pneumonitis. 6\. Uncontrolled infection, including active tuberculosis, or HBV, HCV, or HIV infection considered unsuitable for enrollment by the investigator. Patients with markedly elevated HBV DNA who are not receiving appropriate antiviral treatment are excluded. 7\. Another malignancy within the previous 5 years, except adequately treated low-risk malignancies such as basal cell carcinoma of the skin or carcinoma in situ of the cervix. 8\. Known active central nervous system metastases. Previously treated brain metastases may be permitted if radiographically stable for ≥4 weeks and systemic corticosteroids have been discontinued for \>2 weeks. 9\. Uncontrolled hypertension despite antihypertensive treatment, defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg. 10\. Abnormal coagulation, including INR \>2.0 or prothrombin time \>16 seconds, a bleeding tendency, or current thrombolytic or anticoagulant therapy. Prophylactic low-dose aspirin or low-molecular-weight heparin is permitted. 11\. Any bleeding event of CTCAE version 5.0 grade 2 or higher within 4 weeks before the first dose. 12\. Imaging evidence of tumor invasion of major blood vessels or, in the investigator's judgment, a very high risk of invasion of major blood vessels resulting in fatal hemorrhage during treatment. 13\. An arterial or venous thrombotic event within 6 months before the first dose, including cerebrovascular accident, transient ischemic attack, cerebral hemorrhage, cerebral infarction, deep-vein thrombosis, or pulmonary embolism. 14\. Radiation enteritis caused by pelvic radiotherapy received within 12 months before study treatment. 15\. Active infection, unexplained fever ≥38.5°C within 7 days before treatment, or baseline white blood cell count \>15 × 10\^9/L. 16\. Known interstitial lung disease, evidence or history of noninfectious pneumonitis requiring corticosteroid treatment, or any condition that may interfere with the detection or management of suspected drug-related pulmonary toxicity. 17\. Clinically significant uncontrolled comorbidity, including New York Heart Association class III-IV heart failure, recent myocardial infarction or unstable angina, severe arrhythmia, or poorly controlled hypertension. 18\. History of severe hypersensitivity to adebrelimab, trastuzumab rezetecan, or any component or excipient of either study drug. 19\. Pregnant or breastfeeding women. 20. Any other condition that, in the investigator's judgment, may affect participant safety, efficacy assessment, or protocol compliance, such as severe psychiatric illness or inability to attend regular follow-up.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathological Response Rate | At 8 weeks (±2 weeks) after completion of radiotherapy | The percentage of participants whose pathological stage is downstaged to non-muscle-invasive disease (ypT0, ypTa, ypTis, or ypT1), as confirmed by cystoscopic biopsy or diagnostic transurethral resection of the bladder tumor. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival (EFS) | From treatment initiation until the first qualifying event or last disease assessment, up to 33 months | Time from treatment initiation to the first occurrence of disease progression precluding surgery, local or distant recurrence, or death from any cause. |
| Overall Survival (OS) | From signing informed consent until death or last known alive date, up to 33 months | Time from signing informed consent to death from any cause. |
| Bladder Preservation Rate | From treatment initiation through the end of follow-up, up to 33 months | Percentage of participants who retain their native bladder without undergoing radical cystectomy during the follow-up period. |
| 1-Year and 2-Year Bladder Event-Free Survival Rates | At 1 year and 2 years after treatment initiation | The percentages of participants who retain their native bladder without muscle-invasive recurrence, lymph node or distant metastasis, salvage radical cystectomy, or bladder cancer-related death. |
| Incidence and Severity of Adverse Events | From the first dose of study treatment through 90 days after the last dose | The incidence and severity of adverse events and serious adverse events, assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. |
Countries
China
Contacts
CONTACTWen Song
PRINCIPAL_INVESTIGATORShaogang Wang
Tongji Hospital
Outcome results
None listed