RC48-ADC in Adjuvant/Salvage Treatment of HER2 Positive Non-muscle-invasive Bladder Cancer

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of intravenous RC48-ADC in adjuvant/salvage treatment of HER2 positive high-risk non-muscle-invasive bladder cancer.

Detailed Description
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This study is a multicenter phase II study, which aims to evaluate the efficacy and safety of intravenous RC48-ADC in adjuvant/salvage treatment of HER2 positive high-risk non-muscle-invasive bladder cancer.

Official Title
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A Multicenter Phase II Study of RC48-ADC in Adjuvant/Salvage Treatment of HER2 Positive High-risk Non-muscle-invasive Bladder Cancer

Conditions
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Non-muscle Invasive Bladder Cancer

Intervention / Treatment
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* Drug: RC48-ADC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be willing and able to provide written informed consent/assent for the trial. Life expectancy ≥12 weeks. Have a histologically-confirmed diagnosis of high-risk non-muscle-invasive (according to 2023 NCCN guidelines for bladder cancer) transitional cell carcinoma of the bladder. Subjects with tumors of mixed transitional/non-transitional cell histology are allowed, but transitional cell carcinoma must be the predominant histology. Have been treated with adequate BCG therapy and failed (according to 2023 EAU guidelines for NMIBC, for salvage treatment arm). Have elected not to undergo, or are considered ineligible for radical cystectomy, as determined by the treating surgeon. Have tumor tissues for HER2 IHC evaluation and have a HER2 expression score of HER2 2+ or HER2 3+ reviewed by an independent pathologist at the central laboratory. Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. Demonstrate adequate organ function. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to receiving the first dose of study medication. Male subjects of childbearing potential (Section 5.7.2) must agree to use an adequate method of contraception starting with the first dose of study therapy through 6 months after the last dose of study therapy. Exclusion Criteria: Has muscle-invasive (i.e. T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma. Has concurrent extra-vesical (i.e. urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. Has undergone any intervening intravesical chemotherapy or immunotherapy from the time of most recent cystoscopy/TURBT to starting trial treatment. (Note: A single dose of intravesical treatment given as part of the most recent cystoscopy/TURBT, during the screening period, such as with chemotherapy as per local / regional practices, is acceptable.). Allergic to study therapy. Has a known additional malignancy that has had progression or has required active treatment in the last five years. Has an active autoimmune disease that has required systemic treatment in past 2 years. Have diseases that may interfere with the study treatment or severe and uncontrolled concomitant diseases. Has had an allogeneic tissue/solid organ transplant.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Adjuvant RC48-ADC<br>In this arm, RC48-ADC is evaluated in patients with HER2-positive high-risk non-muscle-invasive bladder cancer as an adjuvant treatment. | Drug: RC48-ADC<br>* Patients are treated with RC48-ADC at 2.0 mg/kg as an intravenous infusion over 30-90 minutes (60 minutes is recommended) once every 2 weeks for 12 weeks.<br>|
| Experimental: Salvage RC48-ADC<br>In this arm, RC48-ADC is evaluated in patients with HER2-positive non-muscle-invasive bladder cancer who failed BCG treatment as an adjuvant treatment. | Drug: RC48-ADC<br>* Patients are treated with RC48-ADC at 2.0 mg/kg as an intravenous infusion over 30-90 minutes (60 minutes is recommended) once every 2 weeks for 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 12-month recurence-free survival rate | The probability of patients remaining free of high-risk NMIBC or worse for at least 12 months after first dose of RC48-ADC adjuvant treatment | From treatment initiation to 12 month | 
| 3-month pathological complete response rate | The proportion of patients are negative for urine cytology and cystoscopy at 3 month after first dose of RC48-ADC salvage treatment | From treatment initiation to 3 month | 
| Adverse events | The type, incidence, relatedness, and severity of adverse events | From patient screening to 30 days after end of cycle 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month recurence-free survival rate | The probability of patients remaining free of high-risk NMIBC or worse for at least 6 months after first dose of RC48-ADC adjuvant treatment | From treatment initiation to 6 month | 
| Duration of response | Time from complete response to recurrence of any disease | From time of complete response to up to 60 months | 
| Recurrence-free survival | Time from first dose of RC48-ADC adjuvant treatment to high-risk NMIBC recurrence or worse | From time of first dose of RC48-ADC adjuvant treatment to up to 60 months | 
| Progression-free survival | Time from first dose of RC48-ADC treatment to progression to higher stage or death | From time of first dose of RC48-ADC treatment to up to 60 months | 
| Overall survival | Time from first dose of RC48-ADC treatment to death from any cause | From time of first dose of RC48-ADC treatment to up to 60 months | 
| Quality of life assessed by EQ-5D scale | Assessed by eEuroQoL EQ-5D scale, higher scores mean better outcomes | After every cycle of treatment and 30 days after end of cycle 6 |