Urogenital Neoplasms
Conditions
Brief summary
First-line systemic treatments for bladder cancer are based on a combination of cytotoxic and immunotherapy, sequentially or concomitantly. Immune checkpoint inhibition (ICPI) is a powerful treatment for patients with metastatic urothelial carcinoma (UC). Since 2017, pembrolizumab (anti-PD1) can be offered as a second-line treatment after failure of platinum agents. In patients responding to platinum salts in first-line treatment, it is possible to maintain efficacy with maintenance treatment with another ICPI, avelumab (anti-PDL1). The phase III JAVELIN BLADDER 100 study compared avelumab to supportive care alone after successful platinum-based chemotherapy. At 30 months, 19.3% of patients were still in response compared to only 6.3% in the supportive care arm. However, biomarker analysis on tumor tissue did not show a robust signature on an individual scale. Recently, two phase 3 trials in first-line were presented at the ESMO 2023 congress. The first, in patients who could receive cisplatin-based chemotherapy, found a benefit on overall survival of adding Nivolumab in combination and then maintaining it for two years. The second proposed combined Enfortumab Vedotin and Pembrolizumab versus standard chemotherapy, with an overall survival for the study arm of more than 31 months. These trials confirm the essential role of immunotherapy in urothelial carcinomas. This progress is tempered by toxicity, cost and the lack of data on patient selection and treatment sequence. Although "prognostic" biomarkers have been identified, they cannot guide the choice of therapy, but only predict the expected outcomes, regardless of the treatment; biomarkers capable of predicting clinical benefit ("predictive") are urgently needed. It is therefore essential to identify a predictive signature at the individual level. The study authors have validated an in vitro model of heterotypic spheroids (SPHERTEST) composed of commercial urothelial carcinoma tumor cells and PBMCs from healthy donors. The aim of the study is to validate this model with PBMCs from UC patients to evaluate the effects of immunotherapy on the immune response and on tumor cell survival in vitro. The study hypothesis is that the outcome of the pre-therapeutic test based on a heterotypic spheroid model with PBMC from patients with advanced or metastatic urothelial carcinoma (SPHERTEST) is related to the response to checkpoint inhibitor (CI) treatment.
Interventions
DIAGNOSTIC_TESTSPHERTEST test
The SPHERETEST is an in vitro model of heterotypic spheroids composed of commercial urothelial carcinoma tumor cells and leukocyte mononuclear cells from healthy donors.
Sponsors
Centre Hospitalier Universitaire de Nīmes
Study design
Observational model
CASE_ONLY
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient with histologically proven urothelial carcinoma, in a locally advanced or metastatic situation with indication for immunotherapy. * The patient must have given their free and informed consent and signed the consent form * The patient must be a member or beneficiary of a health insurance plan
Exclusion criteria
* The subject is participating in a category 1 or drug monotherapy interventional study, or is in a period of exclusion determined by a previous study * It is impossible to give the subject informed information * The patient is under safeguard of justice or state guardianship * History of treatment with anti-PD1 or anti-PDL1 or anti-CTLA4 within the year. * Pregnant, parturient or breastfeeding patient.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SPHERTEST measurement of potential therapeutic efficacy | Day 0 | Yes/No. Differential in spheroid size before and after treatment according to the formula: R=M1-M0. R = test results, M0 = average spheroid size without immunotherapy treatment, M1 = average spheroid size with immunotherapy treatment. When R is ≤ 0, SPHERTEST = "yes" or "potential therapeutic efficacy". When R is \> 0, SPHERTEST = "no" or "absence of potential therapeutic efficacy" |
| Progression-free survival | Month 12 | Yes/No according to RECIST criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Presence of an aggressive minority component | Inclusion | Yes/no |
| Type of other component | Inclusion | Micropapillary, microcystic, trophoblastic differentiation, epidermoid differentiation, nested, plasmacytoid, sarcomatoid, rhabdoid, lymphoepitheliomatoid, large cell, undifferentiated or neuroendocrine |
| Tumor grade | Inclusion | WHO grading |
| PD1/PDL1 status | Inclusion | Yes/no |
| PDL1 score | Inclusion | positive/negative |
| Type of metastatic involvement | Inclusion | Locally advanced (= local recurrence, or pelvic lymph node involvement) or Metastatic sites: liver, bone, lung, brain, extrapelvic lymph node, other |
| Primary tumor site | Inclusion | Bladder/Urethra/upper urinary tract/Urethra |
| Hemoglobin level | Inclusion | g/dL |
| Lactate dehydrogenase level | Inclusion | UI/L |
| C-reactive protein level | Inclusion | mg/L |
| Neutrophil count | Inclusion | G/L |
| Lymphocyte count | Inclusion | G/L |
| Number of lines of systemic treatment received in the metastatic phase | Inclusion | 0, 1, 2, ≥3 |
| Type of platinum salt received prior to immunotherapy | Inclusion | Cisplatin or carboplatin |
| Treatment regimen prior to anti-PD1 therapy | Inclusion | Neoadjuvant with progression within 12 months / Adjuvant with progression within 12 months / Initially locally advanced/metastatic |
| Current treatment: whether treatment is combined with another molecule | Inclusion | Cisplatin / entoftumab-vedotin |
| Antibiotics in the previous month | Inclusion | Duration (days) |
| Corticosteroid therapy > 10 mg prednisolone equivalent at immunotherapy initiation | Inclusion | Yes/no |
| Taking an immunosuppressant other than corticosteroid therapy at immunotherapy initiation | Inclusion | Yes/no |
| Any comedication at immunotherapy initiation | Inclusion | Protein pump inhibitors / beta blockers / metformin / statin |
| Patient functioning level | Inclusion | ECOG Performance Status Scale (1-5) |
| BCG vaccine | Inclusion | Yes/no |
| History of auto-immune disease | Inclusion | Yes/no |
| Mitomycin therapy | Inclusion | Yes/no |
| Histology of cells | Inclusion | Pure transitional cells vs predominantly transitional cells |
Countries
France
Contacts
CONTACTNadine Houede
PRINCIPAL_INVESTIGATORNadine Houede
CHU de Nimes
Outcome results
None listed