Investigator Grant (IG) 2022 27746

NCT06341478 | Recruiting

• 1 other identifier: IG-2022-27746
• Study Type: interventional
• Target: 153
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Bladder Cancer

Outcome Measures

Primary Outcomes (3)

• 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

• 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

• 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

Study Arms (4)

Radical cystectomy

ACTIVE COMPARATOR

Radical cystectomy and pelvic lymphadenectomy upfront, according to the standar-of-care management

Drug: various neoadjuvant therapies

Sacituzumab Govitecan

EXPERIMENTAL

SURE-01 trial: 4 courses of sacituzumab Govitecan, intravenously, at the dose of 7.5 mg/Kg on Day 1 and 8, every 21 days.

Drug: various neoadjuvant therapies

Sacituzumab Govitecan + pembrolizumab

EXPERIMENTAL

SURE-02 trial: 4 courses of sacituzumab Govitecan, intravenously, at the dose of 7.5 mg/Kg on Day 1 and 8, every 21 days, added to pembrolizumab, intravenously, at the dose of 200 mg every 21 days, followed by radical cystectomy. After cystectomy, 13 courses of 200 mg pembrolizumab, intravenously, every 21 days.

Drug: various neoadjuvant therapies

Nivolumab + abraxane

EXPERIMENTAL

NureCombo trial: 4 cycles of 360 mg nivolumab, every 3 weeks, added to nab-paclitaxel 125 mg/m2 on days 1 and 8, every 21 days, before radical cystectomy. After cystectomy, 13 courses of 360 mg nivolumab, intravenously, every 21 days.

Drug: various neoadjuvant therapies

Interventions

various neoadjuvant therapies DRUG

Radical cystectomy, Sacituzumab Govitecan (SG), SG + pembrolizumab, nivolumab+abraxane

Nivolumab + abraxane; Radical cystectomy; Sacituzumab Govitecan; Sacituzumab Govitecan + pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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)

You may not qualify if:

• Refusal to partecipate to the above studies
• Unavailability of baseline tumor and blood samples

Sponsors & Collaborators

• IRCCS San Raffaele: lead

Study Sites (1)

IRCCS Ospedale San Raffaele

Milan, Mi, 20132, Italy

RECRUITING

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Central Study Contacts

Andrea Necchi, MD

CONTACT

+390226435789; necchi.andrea@hsr.it

Rossella Miotti, PhD

CONTACT

miotti.rossella@hsr.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Post-hoc biomarker analyses of ongoing phase 2 studies

Study Record Dates

• First Submitted: March 19, 2024
• First Posted: April 2, 2024
• Study Start: March 15, 2024
• Primary Completion: March 15, 2026
• Study Completion (Estimated): March 15, 2027
• Last Updated: April 2, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)