| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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. |
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| E.1.1.1 | Medical condition in easily understood language |
| 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. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064467 |
| E.1.2 | Term | Urothelial carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to assess in each cohort and independently the pathological complete response (ypT0) rate of a combination therapy with neoadjuvant durvalumab and chemotherapy (Gemcitabine/Cisplatin or Carboplatin) before surgery in patients with high-risk, localized, non-metastatic urothelial carcinoma of the upper tract. |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives are:
A- To assess pathological partial response rate to treatment.
B- To assess the safety and tolerability to treatment.
C- To evaluate overall survival, bladder recurrence, dissemination at two years follow-up.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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:
o High-grade disease on ureteroscopic tumor biopsy OR
o High-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:
o Absolute neutrophil count ≥ 1500 cells/mm3;
o Platelets count ≥ 100,000 cells/mm3;
o Hemoglobin ≥ 9.0 g/dL;
o Bilirubin ≤ 1.5 the upper limit of normal (ULN) for the institution;
o Aspartase transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN for the institution;
o Alkaline phosphatase ≤ 2.5 ULN for the institution;
o INR 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).
o Cohort 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.
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| E.4 | Principal 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 screening to 90 days after the last dose of durvalumab monotherapy.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
In each cohort and independently the rate of patients who achieved a pathological complete response (PCR) after surgery will be assessed.
Pathological complete response (PCR) is defined as no residual signs of viable tumor cells in tissue samples removed during surgery after treatment (yPT0). 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.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
In each cohort and independently:
A- Rate of patients showing pathological partial response (PaR). PaR is defined as downstaging to neoadjuvant pathologic stage groups ≤ ypT1N0M0 (ypT0-Ta-Tis/T1 disease).
The rate of patients with PaR will be calculated on the subpopulation of patients with ureteroscopic biopsy at diagnosis.
B- Assessment of safety and tolerability 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).
C- The overall survival, bladder recurrence, dissemination will be collected at 2 years follow-up after surgery.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
A : After surgery
B : After treatment
C : at 2 years follow-up after surgery. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| two cohorts of patients based on the renal function status disclosed at inclusion |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Date du gel de base de données |
| Date du gel de base de données |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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