Combining Durvalumab with Chemotherapy for High-risk Urothelial Carcinoma

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

This study is testing if adding an immunotherapy drug called durvalumab to chemotherapy can help people with high-risk bladder cancer do better before surgery.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Centre Hospitalier Universitaire de Nīmes (Academic / other)
• Drugs / interventions: durvalumab, prednisone, chemotherapy
• Locations: 9 sites (Paris, Paris Cx 20 and 8 other locations)
• Trial ID: NCT04617756 on ClinicalTrials.gov

What this trial studies

This study evaluates the effectiveness and safety of combining durvalumab, an immunotherapy drug, with neoadjuvant chemotherapy (Gemcitabine and Cisplatin) in patients with high-risk, localized, non-metastatic urothelial carcinoma of the upper urinary tract. The primary goal is to determine the rate of pathological complete response before patients undergo radical nephrectomy. The study aims to provide additional systemic therapy to improve cancer control and survival rates in this patient population, which traditionally faces poor prognoses after surgery.

Who should consider this trial

Good fit: Ideal candidates are patients with high-grade urothelial carcinoma of the renal pelvis or ureter who are eligible for neoadjuvant therapy.

Not a fit: Patients with non-high-grade urothelial carcinoma or those who cannot tolerate chemotherapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly improve survival rates and reduce cancer recurrence in patients with high-risk urothelial carcinoma.

How similar studies have performed: While there have been few studies on neoadjuvant therapies for upper tract urothelial carcinoma, recent trials have shown promising results for similar approaches in bladder cancer.

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.

Where this trial is running

Paris, Paris Cx 20 and 8 other locations

• Hôpital Bichat-Claude Bernard — Paris, Paris Cx 20, France (Recruiting)
• Institut Paoli Calmette — Marseille, France (Recruiting)
• Hôpital Saint Louis — Paris, France (Recruiting)
• Hôpital Pitié Salpétrière — Paris, France (Recruiting)
• Hôpital Européen Georges Pompidou — Paris, France (Recruiting)
• Centre hospitalier Lyon Sud — Pierre-Bénite, France (Recruiting)
• Centre Eugène Marquis — Rennes, France (Recruiting)
• Hôpital Foch — Suresnes, France (Recruiting)
• Iuct Oncopole — Toulouse, France (Recruiting)

Study contacts

• Study coordinator: Nadine HOUEDE, Pr.

Conditions Urothelial Carcinoma; Cancer; Durvalumab; Gemcitabine; Cisplatin; Chemotherapy