This is an open label, phase I/II clinical trial to evaluate the efficacy and safety of 2
cycles of durvalumab without (Arm A) or with (Arm B) tremelimumab in association with ddMVAC
as neoadjuvant therapy in patients with MIUC.
Patients with MIUC fit to receive cisplatin.
The trial is designed as a non-comparative, open-label phase I/II study.
Divided in two phases:
The run In phase (I) and a phase II study. During the run-in phase, a limited number of
patients (n=12-18) will be treated with durvalumab + ddMVAC or durvalumab + tremelimumab +
ddMVAC (6-9 patients each). If the toxicity rate is acceptable (not higher than 2 out of 6 or
3 out of 9 patients per arm) the study will continue as a randomized phase II study. During
phase II, the efficacy and safety of durvalumab + ddMVAC and durvalumab + tremelimumab +
Combination of checkpoint inhibitors (CPI), durvalumab ± tremelimumab, with neoadjuvant
ddMVAC will improve the pathological complete response (pCR) rate in patients with
muscle-invasive urothelial carcinoma (MIUC). No additional toxicity of the combination CPI +
ddMVAC is expected.
Durvalumab: 1500 mg IV D1 every 28 days Durvalumab will be administered at the hospital every
28 days prior to administration of ddMVAC on D1.
Tremelimumab 75 mg IV D1 every 28 days Tremelimumab will be administered first, with
durvalumab infusion starting approximately 1 hour (maximum 2 hours) after the end of the
Mechanism of response/resistance to neoadjuvant treatment will be assessed by comparing
molecular and immunological tumor profiles before treatment (transurethral resection tumor
samples) and after treatment (cystectomy samples). In addition, circulating tumor DNA (ctDNA)
and urine tumor DNA (utDNA) will be analysed during treatment (ctDNA and utDNA) and after
Immunological profiles will be established using a specific metagene signature for major cell
types of the tumor microenvironment and chemokines, cytokines and regulatory molecules , and
will be validated using relevant markers by immunohistochemistry (IHC) on formalin-fixed
paraffin-embedded (FFPE) tumor sections.
Metabolomic profiling will also be conducted by analyzing metabolites present in urinary
samples with a Proton-based nuclear magnetic resonance (1H-NMR), and correlations with
prognosis, molecular profile or/and with immunological signature determined.
Finally, correlations between tumor pathological factors (e.g., pTNM, nuclear grade, variant
squamous differentiation or sarcomatoid dedifferentiation) and prognosis will be evaluated
using IHC on FFPE tissue sections.
Sample Size: Approximately 120 patients are planned to be included.
Infiltrating Bladder Urothelial Carcinoma
Clinical Study Identifier
Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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