NCT03549715

NEoadjuvant Dose-dense MVAC In cOmbination With Durvalumab and Tremelimumab in Muscle-invasive Urothelial Carcinoma

NEoadjuvant Dose-dense MVAC In cOmbination With Durvalumab (MEDI4736) and Tremelimumab in Muscle-invasive Urothelial Carcinoma

• Status: Unknown
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 121 (actual)
• Sponsor: Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

Study Population: Patients with MIUC fit to receive cisplatin. Study Design: 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 + ddMVAC Research hypothesis: 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. Investigational Product(s): 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 tremelimumab infusion. Translational research: 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 surgery (ctDNA). 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 121 patients are planned to be included.

Conditions

• Infiltrating Bladder Urothelial Carcinoma

Interventions

Type	Name	Description
DRUG	Durvalumab	1500 mg IV D1 every 28 days (2 doses for each patient)
DRUG	Tremelimumab	75 mg IV D1 every 28 days ((2 doses for each patient)
DRUG	MVAC Protocol	1. Methotrexate 30 mg/m2 IV D1 2. Vinblastine 3 mg/m2 IV D1 3. Adriamycin (doxorubicin) 30 mg/m2 IV D1 4. Cisplatin 70 mg/m2 IV D1

Timeline

• Start date: 2018-12-06
• Primary completion: 2024-06-01
• Completion: 2025-09-01
• First posted: 2018-06-08
• Last updated: 2024-03-06

Locations

15 sites across 1 country: France