Study aim and objectives

The aim of this trial is to test the possibility of using drug screens in PDO to guide intravesical instillation.

Overall objective

Currently, the drug for chemotherapeutic instillation after TURBT in patients with intermediate-risk low grade NMIBC is selected based on doctors’- and institutional preferences. Most frequently, Epirubicin or MMC are used. Currently, no comparative studies focus on this patient population between the different drugs and the selection is not based on biological characteristics.

We aim to establish a workflow into the clinical routine, that allows a specific selection of the instilled drug based on molecular characteristics of the respective NMIBC.

The current study will test the use of drug screens in PDO for the prediction of treatment in patients. Therefore, we will test the implementation of drug screen in PDO in the workflow of the daily routine.

Primary objective

The primary objective of this study is to evaluate the rate of successful drug selection by using drug screens in PDO generated from patients with low grade intermediate-risk NMIBC. This will allow to determine the rate of patients in which drug selection can successfully be performed for adjuvant intravesical instillation therapies.

Secondary objectives

Secondary objectives of the trial are to evaluate the rate of recurrence, the recurrence free survival and the progression free survival in this population. Further quality of life and safety of instillation will be assessed.

Ethical approval and consent

The GAIN-INST Trial (NCT05024734) has been approved by swissethics and the district ethical board from Bern (BASEC ID 2021-02369). All included patients have read the study information and signed the informed consent for this trial.

Enrollment and trial design

The Department of Urology at the Hospital Center in Biel is conducting the GAIN-INST Trial in which from September 2022 for two years, patients with intermediate-risk NMIBC are recruited according to the criteria in Table 1. After signing the informed consent, patients will be included. In this clinical single-center phase II trial, patients with primary diagnosis of NMIBC are screened in the outpatient clinic for trial recruitment prior TURBT. Tissue harvested during TURBT is used to generate PDO and perform drug screens. Four weeks after TURBT the identified drug is instilled intravesically once a week for 6 weeks. Thereafter, patients are followed according to the standard of care by cystoscopy (Fig. 1). The study is completed after a follow-up of two years, while clinical follow-up will continue to at least 5 years, respectively.

Table 1 Inclusion and exclusion criteriaFig. 1Sample size

The alternative hypothesis states that a successful drug prediction using drug screens in PDO is possible in more than 65% of cases. Sample size was determined using a one sample test. The null hypothesis that a drug prediction will only be possible in 65% of patients will be tested against a one-sided alternative (that the proportion is larger than 65%). Assuming that the real proportion is 85%, a sample of 31 participants should show a statistically significant result at 5% significance and 80% power using an exact binomial test. Assuming an early termination of 10% of patients, a total number of 34 patients will have to be included. Thus, the study will recruit 31 patients that have completed the full 6 instillation cycles.

Tissue sampling, PDO generation and drug treatment

During surgery, cold cup biopsies will be harvested, digested to single cells and plated organoids are allowed to form. Thereafter, PDO are dissociated to single cells, plated and formed after 48 h. These PDO are then exposed to the compounds in the following conditions: untreated (medium) or treated (0.1% DMSO vehicle control, and 4 drugs that are currently used for intravesical instillation (Epirubicin, Mitomycin C, Gemcitabine and Docetaxel). Compound effect is then measured after 48 h by the CellTiterGlo 3D reagent from Promega measuring luminescense. For intravesical instillation, only these four drugs will be used. However, in-vitro testing will eventually include other compounds, dependent on the number of PDO available.

Readout, drug selection and instillation

Each condition will be investigated in triplicates; triplicates and average will be used for drug selection. Only drugs that reduce viability by 50% or more compared to the vehicle, will be considered. In case that more than one drug reduces viability by 50% or more compared to the vehicle, a pairwise Wilcoxon test will be performed between drug and the vehicle. The drug with the lowest p-value will be selected.

Four weeks after TURBT, this selected drug will be used for intravesical instillation. Based on the results of the drug screen in PDO, patients will receive one of either (Epirubicin intravesical (50 mg/50 ml), Mitomycin C intravesical (40 mg/50 ml), Gemcitabine intravesical (1000 ml/50 ml) or Docetaxel intravesical (37.5 mg/50 ml)) once weekly for 6 weeks.

Follow-up and data collection

The patients will be followed by cystoscopy according to the clinical guidelines [1]. The duration of follow-up as part of the clinical trial is done for 2 years after TURBT. However, our institutional guidelines for non-muscle invasive bladder cancer include regular follow-up visits after primary treatment until 5 years after TURBT.

The CRF will be electronic. All data requested on the eCRF must be recorded and the recorded data should be consistent with the source documents or the discrepancies should be explained. The Investigator ensures the accuracy, completeness, and timeliness of the data reported in the eCRF and all other required reports. Generally, the eCRF should be completed within one week of completion of a participant’s visit/ follow-up phone call.

The CRFs in this trial are implemented electronically using a dedicated electronic data capturing (EDC) system (REDCap ®, web-address: redcap.ctu.unibe.ch). The EDC system is activated for the trial only after successfully passing a formal test procedure. All data entered in the eCRF are stored on a Linux server in a dedicated Oracle database.

Statistical methods for primary and secondary outcomes

The predictive potential of biomarkers for the primary and secondary outcome will be analysed using logistic regression.

Missing data is expected to occur due to drop-outs. The amount and reason of missing data will be reported for all outcomes. For survival outcomes drop-outs will be censored at the time of the drop-out.

Data monitoring

For quality control of the study conduct and data retrieval, monitoring will be performed according to a monitoring plan determined by the Clinical Trial Unit from the University of Bern. Any findings and comments will be documented in site visit reports and communicated to the Sponsor-Investigator as applicable. Site staff will support the Monitor in his/ her activities. All source data and relevant documents will be accessible to Monitors and questions of Monitors are answered during site visits. All involved parties will keep participant data strictly confidential.