Investigator Grant (IG) 2022 27746 - Trial NCT06341478

Timeline & Enrollment

Primary Outcome

Predictors of immune response to experimental combination therapies in MIBC.,Genomic predictors of response to experimental combination therapies in MIBC.,Transcriptomic predictors of response to experimental combination therapies in MIBC.

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.

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