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

Gemcitabine

Carboplatin

Cisplatin

Immunomodulating Agents

Durvalumab

This is a single arm including 2 different cohorts : Cohort 1 includes patients on 40mg/ML Gemcitabine/50mg Cisplatin used in combination with 50 mg/mL of intravenous Durvalumab (laboratory code MEDI 4736) every 3 weeks for a total of 4 cycles and Cohort 2 includes patients on 40mg/ML Gemcitabine/450mg Carboplatin used in combination with 50 mg/mL of intravenous Durvalumab (laboratory code MEDI 4736) every 3 weeks for a total of 4 cycles..

Chemotherapy using either a combination of Gemcitabine/Cisplatin and neoadjuvant immunotherapy therapy with Durvalumab (MEDI 4736) or Chemotherapy with either Gemcitibine/Carboplatin and neoadjuvant immunotherapy therapy with Durvalumab (MEDI 4736)

Patients receiving neoadjuvant therapy before radical nephrectomy

Nadine HOUEDE, Pr.

Annissa MEZGARI

Evanguelos XYLINAS

Gwénaëlle Gravis

Alexandra Masson-Lecomte

Morgan ROUPRET, PUPH

François Audenet

Sophie TARTAS

Brigitte LAGUERRE

Yann Neuzillet

Damien POUESSEL

Following radical nephrectomy (RNU) for upper tract urothelial carcinoma (UTUC) most patients face a poor prognosis. Indeed, patients who have undergone RNU for UTUC have 5-year recurrence-free and cancer specific survival probabilities of 69% and 73% respectively.

The primary objective of this study is to assess the pathological complete response rate to combination therapy with neoadjuvant durvalumab and chemotherapy (Gemcitabine/Cisplatin) before surgery in patients with high-risk, localized, non-metastatic urothelial carcinomas of the upper tract.

Following radical nephrectomy (RNU) for upper tract urothelial carcinoma (UTUC) most patients face a poor prognosis. Indeed, patients who have undergone RNU for UTUC have 5-year recurrence-free and cancer specific survival probabilities of 69% and 73% respectively. Additional systemic therapy therefore seems justified for prolonged cancer control. However, there have been very few studies on neoadjuvant/adjuvant therapies in UTUC. Recently, the UK's multicentric POUT trial reported the benefits of adjuvant chemotherapy in UTUC patients. Level 1 evidence has been provided for neoadjuvant therapy for urothelial carcinoma of the bladder via meta-analysis in 2005 but there are also several arguments for systemic therapy in this context especially as most patients lose the function of one kidney and cannot receive nephrotoxic cisplatin-based chemotherapy. Urothelial carcinoma of the upper tract have a different genetic background from carcinomas of the lower tract. The investigators hypothesized that there would be a greater occurrence of lower pathological stages among study group patients who receive neoadjuvant combined Durvalumab/Gemcitabine/Cisplatin or Carboplatin prior to RNU compared to the current literature (Gregg et al. 2018, Almassi et al. 2018). The primary objective is to assess the pathological complete response rate (ypT0) in each cohort and independently of a combination therapy with neoadjuvant durvalumab and chemotherapy (Gemcitabine/Cisplatin) before surgery in patients with high-risk, localized, non-metastatic urothelial carcinomas of the upper tract.Secondary objectives include: assessing partial response rate to treatment, assessing the safety and tolerability of the treatment and evaluating the overall survival, bladder recurrence and dissemination at two years of follow-up.

Patients with an estimated glomerular filtration rate equal to or over 60 ml/min./1.73² (cohort 1) will receive treatment combining Durvalumab and gemcitabine with Cisplatin.

Patients with an estimated glomerular filtration rate of under 60 ml/min./1.73² and over 40 ml/min./1.73² (cohort 2) will receive treatment combining Durvalumab and gemcitabine with Carboplatin.

Safety & Efficacy of Durvalumab+Neoadjuvant Chemotherapy for High-risk Urothelial Carcinoma of the Upper Urinary Tract

Safety & Efficacy of Neoadjuvant Immunotherapy With Durvalumab (MEDI 4736) Combined With Neoadjuvant Chemotherapy (Gemcitabine/Cisplatin or Gemcitabine/Carboplatin) in Patients With Operable, High-risk, Localized Urothelial Carcinoma of the Upper Urinary Tract

Via computed tomographic urography, tumor classification will be performed using the 2017 TNM classification for upper urothelial tract carcinomas. High-risk UTUC is defined by risk stratification following EAU guidelines. Endoluminal filling defects surrounded by opacified urine will be considered as non-infiltrative lesions corresponding to Stage T1. Focal thickening of the urethral wall or renal pelvis = Stage T2. Fat infiltration in front of the parietal thickening or infiltration of kidney tissue = Stage T3.

After surgery, paraffin-embedded tissues and tissues frozen to -80° obtained during surgery will be evaluated by Ventana 623 assay. The PD-L1 status of both tumor cells and immune cells will be recorded.

The overall survival rate of patients in Cohort 1 will be noted following a phone-call to the patient's home. If the patient has died, information regarding the cause of death will be sought from the INSERM's Cepi-DC file (where all records of deceased patients are kept).

The overall survival rate of patients in Cohort 2 will be noted following a phone-call to the patient's home.If the patient has died, information regarding the cause of death will be sought from the INSERM's Cepi-DC file (where all records of deceased patients are kept).

A phone-call to the patient's home will be made and any bladder recurrence will be noted.

A phone-call to the patient's home will be made and any tumor dissemination will be noted.

For Cohort 1 (patients on treatment combining Durvalumab and Gemcitabine associated with Cisplatin) the rate of patients with pathological complete response will be calculated and presented with associated 95% confidence interval on the subpopulation of patients with ureteroscopic biopsy at diagnosis.Pathological complete response is defined as no residual signs of viable tumor cells in tissue samples removed during surgery after treatment. To find out if there is a pathologic complete response, a pathologist will perform an evaluation of the tissue samples under a microscope to see if there are still cancer cells left after the treatment.

For Cohort 2 (patients on treatment combining Durvalumab and Gemcitabine associated with Carboplatin) the rate of patients with pathological complete response will be calculated and presented with associated 95% confidence interval on the subpopulation of patients with ureteroscopic biopsy at diagnosis.Pathological complete response is defined as no residual signs of viable tumor cells in tissue samples removed during surgery after treatment. To find out if there is a pathologic complete response, a pathologist will perform an evaluation of the tissue samples under a microscope to see if there are still cancer cells left after the treatment.

Pathological partial response is defined as downstaging to neoadjuvant pathologic stage groups ≤ ypT1N0M0 (ypT0-Ta-Tis/T1 disease).The rate of patients with partial pathological response will be calculated on the subpopulation of patients with ureteroscopic biopsy at diagnosis.

The safety and tolerability of treatment will be assessed by analysing and interpreting Common Terminology Criteria for Adverse Event (CTCAE) until surgery using the National Cancer Institute, Division of Cancer Treatment and Diagnosis (DCTD) listing of CTCAE (NCI CTCAE V5.0).

The overall Survival rate of Cohort 1 patients will be collected.

Bladder recurrence and dissemination in Cohort 1 patients will be collected.

The overall Survival rate of Cohort 2 patients will be collected.

Bladder recurrence and dissemination will be collected.

The numbers of each type of blood cell and platelets will be measured per McL

A basic metabolic panel will be run to measure Na, K, Cl and Protein levels.

- Hepatic workup: Aspartate Aminotransferase (AST) concentration will be measured in IU/L.

- Hepatic workup: Alanine Aminotransferase (ALT) concentration will be measured in IU/L.

- Hepatic workup: Gamma-Glutamyl Transferase (GGT) concentration will be measured in IU/L.

- Hepatic workup: Lactate Dehydrogenase (LDH) concentration will be measured in IU/L.

- Hepatic workup: Alkaline Phosphatase (ALP) concentration will be measured in IU/L.

- Hepatic workup: Bilirubin (free/conjugated) concentration will be measured il micromoles/L

- Hepatic workup: bilirubin (free/conjugated) concentration will be measured in micromoles/L.

Creatine Phosphokinase will be measured in IU/L. usually between 60 and 400 IU/L

A thyroid stimulating test (total T4 test) will be made to measure the thyroxine concentration in the patient's blood.

Cortisol (serum) levels will be measured at 8 a.m. only (i.e. one cycle out of two) to check whether the adrenal glands are functioning correctly. Normal levels for adults in the morning are :

5-25 mcg/dL (138-690 nmol/L) or 5-23 mcg/dL (138-635 nmol/L) for elderly patients.

C-reactive protein will be measured in mg/L. For a standard CRP test, a normal reading is less than 10 milligram per liter (mg/L).

Urinary balance: via a cytobacteriological examination, the protein/creatinine ratio will be calculated as follows:

(Urine protein(g/L) X 1000)/Urine creatinine(mmol/L)

Serum N-BNP and troponin concentrations will be measured. These are biomarkers of heart failure. N-BNP is measured in pg/mL and troponin is measured in ng/mL.

Serum N-BNP and troponin concentrations will be measured.These are biomarkers of heart failure. N-BNP is measured in pg/mL and troponin is measured in ng/mL.

Hepatic workup: Aspartate Aminotransferase (AST) concentration will be measured in IU/L..

Hepatic workup: Aminotransferase (ALT) concentration will be measured in IU/L.

Hepatic workup: Gamma-Glutamyl Transferase (GGT) concentrations will be measured in IU/L.

Hepatic workup: Lactate Dehydrogenase (LDH) concentration will be measured in IU/L.

Hepatic workup: Alkaline Phosphatase (ALP) concentration will be measured in IU/L.

Hepatic workup: Bilirubin (free/conjugated) concentration will be measured in micromoles/L

- Hepatic workup: Aspartate Aminotransferase (AST) concentration will be measured.

- Hepatic workup: Bilirubin (free/conjugated) concentration will be measured in micromoles/L.

- Creatine Phosphokinase will be measured in IU/L. Normal values are usually between 60 and 400 IU/L

- Creatine Phosphokinase will be measured in IU/L. usually between 60 and 400 IU/L

- Urinary balance: via a cytobacteriological examination, the protein/creatinine ratio will be calculated as follows: (Urine protein(g/L) X 1000)/Urine creatinine(mmol/L)

- Hepatic workup: Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Gamma-Glutamyl Transferase (GGT), Lactate Dehydrogenase (LDH), Alkaline Phosphatase (ALP) and bilirubin (free/conjugated) concentrations will all be measured.

Creatine Phosphokinase Creatine Phosphokinase will be measured in IU/L. usually between 60 and 400 IU/L

Spots Global Cancer Trial Database for patients receiving neoadjuvant therapy before radical nephrectomy