New Models for the Evaluation of Preclinical Treatment for Urothelial Carcinomas of the Upper Excretory Tract. (CICLOP)

Development of New Models for the Evaluation of Preclinical Treatment for Urothelial Carcinomas of the Upper Excretory Tract.

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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Study Overview

• Status: Recruiting
• Conditions: Tumor; Xenograft Model; Upper Urinary Tract Urothelial Carcinoma; Nephroureterectomy

• Study Type: Observational
• Enrollment (Anticipated): 20

Contacts and Locations

• Study Contact: Name: Nadine HOUEDE, Pr.; Phone Number: +33 4.66.68.33.01; Email: nadine.houede@chu-nimes.fr
• Study Contact Backup: Name: Anissa MEGZARI, Mme.; Phone Number: 04.66.68.42.36; Email: drc@chu-nimes.fr

Study Locations

• France
  • Gard
    • Nîmes, Gard, France, 30029
      • Recruiting
      • Centre Hospitalier Universitaire de Nīmes
      • Contact: Anissa MEZGARI

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• 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.

Description

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.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Histological characteristics of patient-derived xenograft models after staining.	Microscopic observation of cells after staining with hematoxylin and eosin	1-6 months after harvesting
Study of genomes of tumor specimens	Exome sequencing of DNA cells isolated from original patient tumor specimens.	1-6 months after harvesting
Alterations in the genomes of patient-derived xenograft tumor models	Exome sequencing of DNA cells isolated from patient-derived xenograft tumor models.	1-6 months after harvesting
Alterations in the genomes of patient-derived cell line models	Exome sequencing of DNA cells isolated from patient-derived cell line models.	1-6 months after harvesting
Study of the transcriptome of patient tumor specimens.	RNA-sequencing of cells isolated from patient tumor specimens.	1-6 months after harvesting
Transcriptome of the patient-derived xenograft tumor models.	RNA-sequencing of cells isolated from patient-derived xenograft tumor models.	1-6 months after harvesting
Transcriptome of the patient-derived cell line models.	RNA-sequencing of cells isolated from patient-derived cell line models.	1-6 months after harvesting

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity to Cisplatin: patient-derived cell line models	The MIC 50 test (Minimum Inhibitory Concentration required for cell growth to be inhibited by 50%) will be used in vitro to test the tumor cells' response to Cisplatin.	6-8 months after harvesting
Sensitivity to Carboplatin: patient-derived cell line models	The MIC 50 test (Minimum Inhibitory Concentration required for cell growth to be inhibited by 50%) will be used in vitro to test the tumor cells' response to Carboplatin.	6-8 months after harvesting
Sensitivity to Oxaliplatin: patient-derived cell line models	The MIC 50 test (Minimum Inhibitory Concentration required for cell growth to be inhibited by 50%) will be used in vitro to test the tumor cells' response to Oxaliplatin.	6-8 months after harvesting
Sensitivity to Gemcitabin: patient-derived cell line models	The MIC 50 test (Minimum Inhibitory Concentration required for cell growth to be inhibited by 50%) will be used in vitro to test the tumor cells' response to Gemcitabin.	6-8 months after harvesting
Tumor size in non-treated patient-derived xenograft models	The volume of tumors will be measured in mm3.	1-6 months after harvesting
Sensitivity to Cisplatin: tumor size in treated patient-derived xenograft models	To test the tumor cells' response to Cisplatin in xenograft models, the volume of tumors will be measured in mm3 and compared with the volume of tumors in the non-treated control group.	6-8 months after harvesting
Sensitivity to Cisplatin: tumor growth rate in patient-derived xenograft models	To test the tumor cells' response to Cisplatin in xenograft models, the Tumor Growth Inhibition index, which is defined as (1 - (mean volume of treated tumors)/(mean volume of control tumors)) × 100% will be used.	6-8 months after harvesting
Sensitivity to Carboplatin: tumor size in treated patient-derived xenograft models	To test the tumor cells' response to Carboplatin in xenograft models, the volume of tumors will be measured in mm3 and compared with the volume of tumors in the non-treated control group.	6-8 months after harvesting
Sensitivity to Carboplatin: tumor growth rate in treated patient-derived xenograft models	To test the tumor cells' response to Carboplatin in xenograft models, the Tumor Growth Inhibition index, which is defined as (1 - (mean volume of treated tumors)/(mean volume of control tumors)) × 100% will be used.	6-8 months after harvesting
Sensitivity to Oxiplatin: tumor size in treated patient-derived xenograft models	To test the tumor cells' response to Oxiplatin in xenograft models, the volume of tumors will be measured in mm and compared with the volume of tumors in the non-treated control group.	6-8 months after harvesting
Sensitivity to Oxiplatin: tumor growth rate in treated patient-derived xenograft models	To test the tumor cells' response to Oxiplatin in xenograft models, the Tumor Growth Inhibition index, which is defined as (1 - (mean volume of treated tumors)/(mean volume of control tumors)) × 100% will be used.	6-8 months after harvesting
Sensitivity to Gemcitabine: tumor size in treated patient-derived xenograft models	To test the tumor cells' response to Gemcitabine in xenograft models, the tumor volume will be measured in mm3 and compared with the volume of tumors in the non-treated control group.	6-8 months after harvesting
Sensitivity to Gemcitabin: tumor growth rate in treated patient-derived xenograft models	To test the tumor cells' response to Gemcitabin in xenograft models, the Tumor Growth Inhibition index, which is defined as (1 - (mean volume of treated tumors)/(mean volume of control tumors)) × 100% will be used.	6-8 months after harvesting

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patients' gender	The sex of patients will be recorded at the inclusion as Male/Female/Transgender	Day 0
Patients' age	The age of patients will be recorded at the inclusion in years	Day 0
Primitive tumor site	The site of the patient's primitive tumor will be recorded at the inclusion	Day 0
Infiltrative tumor	The tumor will be noted as infiltrative or not (YES/NO) at the inclusion.	Day 0

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nīmes
• Collaborators: INSERM U1194, Institut de Recherche en Cancérologie de Montpellier, Campus Val d'Aurelle, 34298 Montpellier cedex 5
• Investigators: Principal Investigator: Nadine HOUEDE, Pr., CHU de Nîmes

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2021
• Primary Completion (Anticipated): September 1, 2023
• Study Completion (Anticipated): March 1, 2024

Study Registration Dates

• First Submitted: June 22, 2021
• First Submitted That Met QC Criteria: June 22, 2021
• First Posted (Actual): June 29, 2021

Study Record Updates

• Last Update Posted (Actual): September 28, 2022
• Last Update Submitted That Met QC Criteria: September 27, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Transitional Cell
• Other Study ID Numbers: NIMAO/2020-2/NH01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No