Investigator Grant (IG) 2022 27746

Bladder Cancer Clinical Trial

Official title:

Understanding Tumor and Immune Dynamics and Predicting Response to Various Perioperative Therapies in Patients With Muscle-invasive Bladder Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06341478
• Other study ID #: IG-2022-27746
• Status: Recruiting
• Phase: N/A
• Start date: March 15, 2024
• Est. completion date: March 15, 2027

Study information

• Verified date: March 2024
• Source: IRCCS San Raffaele
• Contact: Andrea Necchi, MD
• Phone: +390226435789
• Email: necchi.andrea[@]hsr.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

Muscle-invasive bladder cancer (MIBC) is a systemic disease as >40% of patients (pts) ultimately develop recurrence after radical cystectomy (RC). For pts who cannot receive or refuse cisplatin-based chemotherapy there is no standard-of-care neoadjuvant therapy. Single-agent pembrolizumab, given neoadjuvantly in patients with T2-4N0M0 MIBC, documented a 42% pathologic complete response-rate (ypT0N0) in a previous AIRC-supported trial (PURE-01, NCT02736266; PMID: 30343614). However, there is a huge proportion of pts who do not benefit from single-agent immunotherapy. Antibody-drug conjugates (ADC) represent the next wave of MIBC treatment revolution. An umbrella of various neoadjuvant therapies including the ADC Sacituzumab govitecan (SG), SG plus pembrolizumab, and chemoimmunotherapy combination has been established to improve our knowledge on MIBC biology and to improve the outcomes.

Hypothesis:

By developing a robust biomarker program associated with therapeutic benefit of novel therapies or their combinations, along with an imaging biomarker development, the investigators will be able to identify suitable tumor characteristics for personalizing perioperative therapies in MIBC, coupled with the possibility to predict the pathological response to treatment.

Aims:

The project is aimed at characterizing the tumor and microenvironment characteristics of muscle-invasive bladder cancer, with a special focus on their changes induced by various neoadjuvant therapies preceding radical cystectomy.

The investigators will aim to evaluate the tumor and immune profile on matched pre- vs post-therapy samples and noninvasively monitor the response to treatment with the use of radiological assessments.

Experimental design:

The investigators will access tumor samples from matched pre-therapy (transurethral resection of the bladder tumor) and post-therapy (radical cystectomy) surgical interventions. They will also analyze the imaging analyses of combined bladder multiparametric MRI/Fluorodeoxyglucose Positron Emission Tomography (PET) scans pre-post neoadjuvant therapies, and will associate the data with the pathological response to treatment, expanding our previously reported work (PMID: 31882281).

Biomarker analyses will include the following: i.) multiplex immunofluorescence assays will allow the investigators defining the immune contexture of tumor lesion; ii.) multiparametric flow cytometry will allow the phenotypic and functional analysis of peripheral blood cells at single cell level; iii.) a whole transcriptome assay will enable investigators to assign specific molecular subtypes to pathological response and outcome, as previously reported (PMID: 33785257; 32165065).

Expected results:

The investigators will expect to identify the tumor characteristics and immune-profiling enabling them to delineate the selection of patients most suited for certain novel perioperative therapies, thus anticipating the developments in clinical research that are being conducted worldwide in MIBC.

The investigators will be also able to develop noninvasive tools for pathological complete response identification, thus enabling them to develop a next-generation of clinical trials aimed at sparing any radical local therapy on the bladder tumor.

Impact on cancer:

In principle, the present personalized strategy yields the potential to enhance the therapeutic standards achievable with RC alone as well as with single-agent immunotherapy and RC.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 153
• Est. completion date: March 15, 2027
• Est. primary completion date: March 15, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Inclusion in NureCombo (NCT04876313), SURE-01 (NCT05226117), and SURE-02 (NCT05535218) clinical trials or candidates to radical cystectomy as per routine clinical practice.

2. Histopathologically-confirmed urothelial carcinoma (UC). 3. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 4. Clinical stage T2-T4N0M0, muscle-invasive bladder cancer (MIBC)

Exclusion Criteria:

1. Refusal to partecipate to the above studies

2. Unavailability of baseline tumor and blood samples

Related Conditions & MeSH terms

• Bladder Cancer
• Urinary Bladder Neoplasms

Intervention

Drug:
• various neoadjuvant therapies
Radical cystectomy, Sacituzumab Govitecan (SG), SG + pembrolizumab, nivolumab+abraxane

Locations

Country	Name	City	State
Italy	IRCCS Ospedale San Raffaele	Milan	Mi

Sponsors (1)

Lead Sponsor	Collaborator
IRCCS San Raffaele

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Predictors of immune response to experimental combination therapies in MIBC.	Proportion of polymorphonuclear (PMN) cells, PMN-myeloid-derived suppressor cells (MDSCs), and intermediate monocytes (CD14+CD16+) in baseline blood samples of pathological complete responders compared to non-complete responders (pathological partial responders, pPR) and pathological nonresponders (pNR, ypT=2N0 and ypN+).	Baseline (pre-therapy) to radical cystectomy
Primary	Genomic predictors of response to experimental combination therapies in MIBC.	Proportion of gene mutations and fusions in baseline tumor samples of pathological complete responders compared to non-complete responders (pathological partial responders, pPR) and pathological nonresponders (pNR, ypT=2N0 and ypN+).	Baseline (pre-therapy) to radical cystectomy
Primary	Transcriptomic predictors of response to experimental combination therapies in MIBC.	Proportion of single gene or gene pathways signature scores in baseline tumor samples of pathological complete responders compared to non-complete responders (pathological partial responders, pPR) and pathological nonresponders (pNR, ypT=2N0 and ypN+).	Baseline (pre-therapy) to radical cystectomy