Safety & Efficacy of Durvalumab+Neoadjuvant Chemotherapy... | NCT04617756

Name	Class
Pitié-Salpêtrière Hospital	OTHER
Bichat Hospital	OTHER
Hopital Foch 92151 Suresnes	UNKNOWN
Institut Paoli-Calmettes

Description Module

Detailed Description

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.

Label	Type	Description	Intervention Names
Durvalumab+Gemcitabine/Cisplatin or with Gemcitabine/Carboplatin	Experimental	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..	Drug: Patients receiving neoadjuvant therapy before radical nephrectomy

Name	Type	Description	Arm Group Labels	Other Names
Patients receiving neoadjuvant therapy before radical nephrectomy	Drug	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)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Pathological complete response in Cohort 1	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.	Week 14 - 18
Pathological complete response in Cohort 2	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.	Week 14 - 18

Secondary Outcomes

Measure	Description	Time Frame
Partial pathological response in Cohort 1	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.	Week 3

Other Outcomes

Measure	Description	Time Frame
Tumor staging in Cohort 1	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.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Patient has been correctly informed and has given signed consent.
Patient is covered by a health insurance scheme.
Patients aged over 70 must have a G8 score (Soubeyran et al. 2014) of at least 14.
Patient's body weight must be over 30kg
Patient has high-grade urothelial carcinoma of the renal pelvis or ureter confirmed histologically (uteroscopic biopsy) or cytologically (urine cytology).
Presence of divergent histologies (i.e. squamous cell tumour, adenocarcinoma, small cell carcinoma, micropapillary variant) may also give rise to inclusion if there is a high prevalence (over 90%) of a urothelial component.
Presence of EITHER high-grade disease on the uteroscopic tumor biopsy
OR Presence of high-grade disease on urine cytology AND infiltrative aspect of renal pelvis/ ureteral wall on the CT scan (presence of hydronephrosis will be considered invasive by definition) with negative cystoscopy.
Or in the absence of histological evidence, the opinion of the multidisciplinary consultation meeting (RCP) will prevail for the analysis of the imaging and the potential inclusion of the patient in the study
No prior systemic therapies.
ECOG performance status 0 to 1.
M0 No or N1 disease on CT scan.
- Required initial laboratory values :
Absolute neutrophil count of over 1500 cells/mm²
Platelet count of over 100,000 cells/mm3
Hemoglobin over 9.0 g/dL
Bilirubin below 1.5 times the Upper Limit of Normal for the institution
Aspartase transaminase (ASAT) and Alanine transaminase (ALAT) below 2.5 x the Upper Limit of Normal for the institution.
Alkaline phosphatase below 2.5 times the Upper Limit of Normal for the institution
INR and aPTT below 1.5 times the Upper Limit of Normal for the institution.
For Cohort 1 : An estimated glomerular filtration rate of over 60ml/min/1.73m² using the CKD-EPI and/or MDRD equation.
For Cohort 2 : An estimated glomerular filtration rate of 40ml to 60ml/min/1.73m² using the CKD-EPI and/or MDRD equation.
Patients with reproductive potential must use an effective method to avoid pregnancy for the duration of the trial.
Patients must have a life expectancy of at least 12 weeks.

Exclusion Criteria:

The patient is participating in another interventional trial;
or is in an exclusion period determined by a previous study;
or is under judicial protection, or is an adult under guardianship
or refuses to sign the consent;
or it is impossible to correctly inform the patient.
The patient is pregnant or breastfeeding.
Concomitant diagnosis of muscle invasive or in situ or high grade non muscle invasive urothelial carcinoma of the bladder.
Evidence of NYHA functional class III or IV heart disease.
Serious intercurrent medical or psychiatric illness, including serious active infection.
Concomitant use of any other investigational drugs.
Diagnosis of immunodeficiency or received systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study registration.
Additional malignancy within last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer that has undergone potentially curative therapy, stable (as defined by PSA change, checked within 30 days) and untreated very low-risk or low-risk prostate cancer defined by current NCCN guidelines. Previous or concomitant history of non-muscle invasive bladder cancer is acceptable.
Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. NOTE: Subjects with vitiligo or resolved childhood asthma/atopy would be an exception. Subjects that require systemic corticosteroids at physiologic doses not exceed 10mg/day of prednisone or its equivalent would not be excluded from the study. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study.
History of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C.
Live vaccine received within 30 days prior to the first dose of trial treatment.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of treatment. Note: Local surgery of isolated lesions for palliative intent is acceptable.
History of allogenic organ transplantation.
Uncontrolled intercurrent illness, including but not limited to, on-going or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.

Name	Role	Phone	Extension	Email
Nadine HOUEDE, Pr.	Contact	+33 4 66 68 33 01		nadine.HOUEDE@chu-nimes.fr
Annissa MEZGARI	Contact	+33 4 66 68 30 52		drc@chu-nimes.fr

PubMed Identifier	Type	Citation	Retractions
39951246	Derived	Houede N, Chevallier T, Audenet F, Thibault C, Neuzillet Y, Abraham C, Masson-Lecomte A, Gauthier H, Gravis G, Pignot G, Tartas S, Ruffion A, Pouessel D, Roumiguie M, Laguerre B, Bensalah K, Xylinas E, Jaffrelot L, Droupy S, Luquiens G, Roupret M. Safety and Efficacy of Neoadjuvant Durvalumab Plus Gemcitabine/Cisplatin or Carboplatin in Patients With Operable High-Risk Upper Tract Urothelial Carcinoma: The iNDUCT-GETUG V08 Trial. J Clin Oncol. 2025 May;43(13):1578-1586. doi: 10.1200/JCO-25-00179. Epub 2025 Feb 14.
37698632

ID	Term
D002295	Carcinoma, Transitional Cell
D009369	Neoplasms

ID	Term
D002277	Carcinoma
D009375	Neoplasms, Glandular and Epithelial
D009370	Neoplasms by Histologic Type