Clinical trial NCT04944550: New Models for the Evaluation of Preclinical Treatment for Urothelial Carcinomas of the Upper Excretory Tract.
Official title: Development of New Models for the Evaluation of Preclinical Treatment for Urothelial Carcinomas of the Upper Excretory Tract.
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Upper Urinary Tract Urothelial Carcinoma
Nephroureterectomy
Tumor
Xenograft Model
Lead sponsor: Centre Hospitalier Universitaire de Nīmes
Sponsor class: OTHER
Collaborators: name: INSERM U1194, Institut de Recherche en Cancérologie de Montpellier, Campus Val d'Aurelle, 34298 Montpellier cedex 5
First posted: 2021-06-29
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: OTHER
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population consists of patients treated consecutively at the Urology Andrology department of Nîmes University Hospital for high-grade carcinomas of the pelvis or renal ureter for whom a total nephroureterectomy has been indicated during a multidisciplinary meeting. The tumor samples used for our study come from specimens removed surgically. Patients must not have undergone any prior systemic treatment.

Brief summary: Upper Urinary Tract Urothelial Carcinomas are rare, aggressive tumors, accounting for 5 to 10% of all urothelial tumors. These include tumors which develop in the renal cavities (renal pelvis, calices) and ureteral tumors. Nephro-ureterectomy is the standard treatment but 80% of patients will have a relapse within 2 years. Only one trial has (Birtle et al. 2020), has shown the interest of postoperative chemotherapy. Neoadjuvant systemic treatment seems particularly interesting for a population which is going to undergo a nephronic loss and therefore reduction in kidney function which is likely to make patients ineligible for cisplatin. In favor of additional immunotherapy, it has been described that upper excretory tract tumors have a high immunogenic potential with a high rate of microsatellite instability.

From surgical samples of patient tumors obtained after nephroureterectomy or biopsy material collected before treatment, we are going to generate patient-derived cell lines and xenograft models in the mouse. A recent publication has demonstrated the feasibility of this approach by specifying that the capture rate of tumor cells is 50% for patient-derived xenografts and 25% for patient-derived cells (Coleman et al. 2020). As tumors harvested from biopsies do not grow in patient-derived xenografts,we plan to graft the biopsies onto chorioallantoic chicken embryo membranes, a model which has never been used for this indication and which is one of the original features of our approach. These three concomitant approaches will allow us to increase our chances of obtaining stable upper urinary tract urothelial carcinoma lines to be used for the screening and identification of new treatments or new combinations of molecules that would benefit patients with upper urinary tract urothelial carcinomas, knowing that very few studies dedicated to this type of cancer have been conducted or published due to the rarity of the disease and the lack of existing models published on the subject of these particular tumors.

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Eligibility criteria: Inclusion Criteria:

* Patients treated consecutively at the Urology Andrology Department of Nîmes University Hospital for high grade carcinoma of the pelvis or renal ureter with an indication for total nephroureterectomy decided during a multidisciplinary meeting.
* Patient with a diagnosis of high-grade urothelial carcinoma of the pelvis or renal ureter confirmed by histology (biopsy, biopsy of the ureteroscopic) or by cytology with the presence of :
* High-grade disease on ureteroscopic biopsy OR ;
* High grade disease on urinary cytology AND infiltrating appearance of the renal pelvic wall / ureter on the scanner (the presence of hydronephrosis will be considered as pervasive by definition) with a negative cytoscopy.

Exclusion Criteria:

* Any patient who has undergone previous systemic treatment.

Primary outcomes:
measure: Histological characteristics of patient-derived xenograft models after staining.
timeFrame: 1-6 months after harvesting
measure: Study of genomes of tumor specimens
timeFrame: 1-6 months after harvesting
measure: Alterations in the genomes of patient-derived xenograft tumor models
timeFrame: 1-6 months after harvesting
measure: Alterations in the genomes of patient-derived cell line models
timeFrame: 1-6 months after harvesting
measure: Study of the transcriptome of patient tumor specimens.
timeFrame: 1-6 months after harvesting
measure: Transcriptome of the patient-derived xenograft tumor models.
timeFrame: 1-6 months after harvesting
measure: Transcriptome of the patient-derived cell line models.
timeFrame: 1-6 months after harvesting
Secondary outcomes:
measure: Sensitivity to Cisplatin: patient-derived cell line models
timeFrame: 6-8 months after harvesting
measure: Sensitivity to Carboplatin: patient-derived cell line models
timeFrame: 6-8 months after harvesting
measure: Sensitivity to Oxaliplatin: patient-derived cell line models
timeFrame: 6-8 months after harvesting
measure: Sensitivity to Gemcitabin: patient-derived cell line models
timeFrame: 6-8 months after harvesting
measure: Tumor size in non-treated patient-derived xenograft models
timeFrame: 1-6 months after harvesting
measure: Sensitivity to Cisplatin: tumor size in treated patient-derived xenograft models
timeFrame: 6-8 months after harvesting
measure: Sensitivity to Cisplatin: tumor growth rate in patient-derived xenograft models
timeFrame: 6-8 months after harvesting
measure: Sensitivity to Carboplatin: tumor size in treated patient-derived xenograft models
timeFrame: 6-8 months after harvesting
measure: Sensitivity to Carboplatin: tumor growth rate in treated patient-derived xenograft models
timeFrame: 6-8 months after harvesting
measure: Sensitivity to Oxiplatin: tumor size in treated patient-derived xenograft models
timeFrame: 6-8 months after harvesting
measure: Sensitivity to Oxiplatin: tumor growth rate in treated patient-derived xenograft models
timeFrame: 6-8 months after harvesting
measure: Sensitivity to Gemcitabine: tumor size in treated patient-derived xenograft models
timeFrame: 6-8 months after harvesting
measure: Sensitivity to Gemcitabin: tumor growth rate in treated patient-derived xenograft models
timeFrame: 6-8 months after harvesting
Other outcomes:
measure: Patients' gender
timeFrame: Day 0
measure: Patients' age
timeFrame: Day 0
measure: Primitive tumor site
timeFrame: Day 0
measure: Infiltrative tumor
timeFrame: Day 0
Locations:
city: Nîmes
country: France
facility: Centre Hospitalier Universitaire de Nîmes
state: Gard
Study officials:
affiliation: CHU de Nimes
name: Nadine HOUEDE, Pr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Birtle A, Johnson M, Chester J, Jones R, Dolling D, Bryan RT, Harris C, Winterbottom A, Blacker A, Catto JWF, Chakraborti P, Donovan JL, Elliott PA, French A, Jagdev S, Jenkins B, Keeley FX Jr, Kockelbergh R, Powles T, Wagstaff J, Wilson C, Todd R, Lewis R, Hall E. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. 2020 Apr 18;395(10232):1268-1277. doi: 10.1016/S0140-6736(20)30415-3. Epub 2020 Mar 5.