Guiding Instillation in Non Muscle-invasive Bladder Cancer Based on Drug Screens in Patient Derived Organoids

Study Overview
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Brief Summary
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From patients with intermediate risk non-muscle invasive bladder cancer tumor (NMIBC) specimens will be harvested during transurethral resection. Fresh specimens will be cultured as patient derived organoids (PDO). After approx. 10 days, PDO are exposed to different drugs that are used as intravesical instillation agents in these patients (epirubicin, mitomycin, gemcitabine, docetaxel). After 2 days of exposure, PDO viability will be measured. The drug with the highest antitumor effect on PDO will be applied as weekly intravesical instillations 6 times. Thereafter, patients are followed according to the standard of care.

Official Title
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Guidance of Adjuvant Instillation in Intermediate Risk Non-muscle Invasive Bladder Cancer by Drug Screens in Patient Derived Organoids. A Single Center, Open-label, Phase II Trial With a Feasibility Endpoint. (GAIN-INST-TRIAL)

Conditions
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Bladder Cancer, Non-muscle Invasive

Intervention / Treatment
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* Drug: Epirubicin
* Drug: Mitomycin
* Drug: Gemcitabine
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Signed Informed Consent Form ECOG performance status of 0 or 1 Histologically confirmed intermediate risk non muscle-invasive urothelial carcinoma of the bladder (pTa low grade) Patients Representative fresh tumor specimen for PDO generation and drug screen Exclusion Criteria: Known previous high grade and/or high risk non muscle-invasive bladder cancer Previous Intravesical biological/immuno (BCG) therapy Pregnancy or nursing Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol Severe infection within 4 weeks prior to cycle 1, day 1 Contraindication for frequent catheterization Voiding dysfunction

Ages Eligible for Study
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Minimum Age: 18 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epirubicin<br>Patients in that PDOs show highest response to this drug in-vitro will be treated with Epirubicin. If no significant drug selection can be performed in-vitro, Epirubicin will be the default for instillation. | Drug: Epirubicin<br>* In PDOs from patients that show highest response to Epirubicin, this drug will be instilled intravesically once weekly for 6 times. Epirubicin is also the default drug, in case of failure of drug prediction in the in-vitro drug screen in PDO. Epirubicin will be used as a concentrate for injection/instillation 2 mg/ml in total 50mg per vial. Prior to use, the concentrate for injection is diluted with 25ml of 0.9% saline solution to obtain the final Solution with 1mg/ml of Epirubicin.<br>|
| Experimental: Mitomycin<br>Patients in that PDOs show highest response to this drug in-vitro will be treated with Mitomycin. | Drug: Mitomycin<br>* In PDOs from patients that show highest response to Mitomycin, this drug will be instilled intravesically once weekly for 6 times. Mitomycin C will be used as 20mg dry powder. Prior to use, the powder will be dissolved in 50ml of 0.9% saline solution according to the manufacturer instructions<br>|
| Experimental: Gemcitabine<br>Patients in that PDOs show highest response to this drug in-vitro will be treated with Gemcitabine. | Drug: Gemcitabine<br>* In PDOs from patients that show highest response to Gemcitabine, this drug will be instilled intravesically once weekly for 6 times. Gemcitabine will be used as 2000 mg/50ml. For intravesical application, 1000mg of gemcitabine (corresponding to 25ml) will be diluted in 25ml 0.9% saline solution, to obtain the gemcitabine concentration of 1000mg/50ml used for instillation.<br>|
| Experimental: Docetaxel<br>Patients in that PDOs show highest response to this drug in-vitro will be treated with Docetaxel. | Drug: Docetaxel<br>* In PDOs from patients that show highest response to Docetaxel, this drug will be instilled intravesically once weekly for 6 times. Docetaxel will be used as 140mg/7ml solution. For intravesical application, 48.825ml of saline will be added to 1.875ml Docetaxel solution (according 37.5mg of Docetaxel). The concentration of this solution is 0.74mg/ml by a total volume of the instillation solution of 50,7.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with successful drug selection | ● To determine the proportion of patients for which a suitable treatment can be identified by drug screens in patient derived organoids This will establish the use of drug screens in PDOs in clinical setting and their implementation in clinical trials. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Side effects | Number of patients with side effects | 24 months | 
| Recurrence rate | Number of patients with recurrence | 42 months | 
| QoL | Quality of life will be determined using the SF-36 questionnaire | 42 months |