Safety and Efficacy of Neoadjuvant immunotherapy with Durvalumab (MEDI 4736) in combination with neoadjuvant chemotherapy (Gemcitabin/Cisplatin or Gemcitabin/Carboplatin) in patients with operable, high-risk, localized urothelial carcinoma of the upper urinary tract.

Phase 1

• Conditions: The patient has a histologically-confirmed (ureteroscopic biopsy) or cytologically(urine cytology)-confirmed diagnosis of high-grade urothelial carcinoma of the renal pelvis or ureter. Presence of divergent histologies (i.e. squamous-cell tumor, adenocarcinoma, small cell carcinoma, micropapillary variant) may be acceptable provided that there is an important prevalence (> 90%) of urothelial component.; MedDRA version: 20.0Level: LLTClassification code 10064467Term: Urothelial carcinomaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2020-001028-32-FR
• Lead Sponsor: CHU DE NIMES

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-09-11
• Last Update Posted: 5 April 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 99

Inclusion Criteria

•The patient has been correctly informed.
•The patient must have given his/her informed and signed consent.
•The patient must be insured or beneficiary of a health insurance plan.
•The patient is at least 18 years old. Patients older than 70 years will be evaluated for fragility with G8 score (Soubeyran et al. 2014). Patients with a G8 score of less than 14 will not be included in the study.
•Body weight > 30 Kg.
•The patient has a histologically-confirmed (ureteroscopic biopsy) or cytologically(urine cytology)-confirmed diagnosis of high-grade urothelial carcinoma of the renal pelvis or ureter. Presence of divergent histologies (i.e. squamous-cell tumor, adenocarcinoma, small cell carcinoma, micropapillary variant) may be acceptable provided that there is an important prevalence (> 90%) of urothelial component.
•Presence of either:
oHigh-grade disease on ureteroscopic tumor biopsy OR
oHigh-grade disease on urine cytology AND infiltrative aspect of renal pelvis/ureteral wall on CT imaging (presence of hydronephrosis will be considered invasive by definition) with negative cystoscopy.
•No prior systemic therapies.
•Patient must be eligible to radical nephroureterectomy surgery
•ECOG performance status 0 to 1.
•M0 disease on CT scan.
•Required initial laboratory values:
oAbsolute neutrophil count = 1500 cells/mm3;
oPlatelets count = 100,000 cells/mm3;
oHemoglobin = 9.0 g/dL;
oBilirubin = 1.5 the upper limit of normal (ULN) for the institution;
oAspartase transaminase (AST) and alanine transaminase (ALT) = 2.5 x ULN for the institution;
oAlkaline phosphatase = 2.5 ULN for the institution;
oINR and aPTT = 1.5 x ULN (this applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose).
oCohort 1: Estimated glomerular filtration rate = 60 ml/min/1.73m2 using the CKD-EPI and/or MDRD equation; Cohort 2: Estimated glomerular filtration rate < 60 ml/min/1.73m2 and = 40 ml/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.
•Patient must have a life expectancy of at least 12 weeks.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 80
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 19

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 history of a unique 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
•Known prior severe hypersensitivity to investigational products or its excipients
•Has received a live vaccine within 30 days prior to the first dose of study drug.

•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 scree

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified