Neoplasms

All Conditions

Rare Diseases

Carcinoma

Carcinoma, Transitional Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Transitional Cell Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Doxorubicin

Liposomal doxorubicin

Methotrexate

Cisplatin

Durvalumab

Vinblastine

Tremelimumab

Antineoplastic Agents, Immunological

Durvalumab + ddMVAC 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.

durvalumab + tremelimumab + ddMVAC 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.

Infusion of ddMVAC will start approximately 1 hour after completion of durvalumab.

1500 mg IV D1 every 28 days (2 doses for each patient)

75 mg IV D1 every 28 days ((2 doses for each patient)

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

MVAC Protocol

Constance THIBAULT, MD

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.

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.

The sample size will be balanced between 2 arms. Initially, 12 patients (6 in each arm) will be included and randomized between durvalumab + ddMVAC (ARM A) or durvalumab + tremelimumab + ddMVAC (ARM B)

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

To determine changes in the molecular profile and immunological signature of the tumor after treatment compared with before treatment.

To identify predictive factors of pCR response to treatment.

To determine changes in the immunological signature of the tumor after treatment compared with before treatment.

Grade ≥ 3 treatment related toxicity rate

pCR rate after ddMVAC + durvalumab ± tremelimumab period

To evaluate the 2-year disease-free survival (DFS) rate.

To evaluate the 2-year overall survival (OS) rate

To evaluate the incidence of adverse events (AEs).

To evaluate the pathologic downstaging rate (defined as the presence of residual tumor ≤T1 on cystectomy, excluding T0).

Spots Global Cancer Trial Database for mvac protocol