Clinical trial NCT04617756: Safety & Efficacy of Durvalumab+Neoadjuvant Chemotherapy for High-risk Urothelial Carcinoma of the Upper Urinary Tract
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Urothelial Carcinoma
Cancer
Keywords: Durvalumab
Gemcitabine
Cisplatin
Chemotherapy
Lead sponsor: Centre Hospitalier Universitaire de Nīmes
Sponsor class: OTHER
Collaborators: name: Pitié-Salpêtrière Hospital
name: Hôpital Bichat-Claude Bernard, 75018 Paris
name: Hopital Foch 92151 Suresnes
name: Institut Paoli-Calmettes
name: European Georges Pompidou Hospital
name: Saint-Louis Hospital, Paris, France
name: Centre Hospitalier Lyon Sud
name: Center Eugene Marquis
name: IUCT ONCOPOLE
First posted: 2020-11-05
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 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.
Primary purpose: TREATMENT

Brief summary: 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.

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.

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.

Primary outcomes:
measure: Pathological complete response in Cohort 1
timeFrame: Week 14 - 18
measure: Pathological complete response in Cohort 2
timeFrame: Week 14 - 18
Secondary outcomes:
measure: Partial pathological response in Cohort 1
timeFrame: Week 3
measure: Partial pathological response in Cohort 2
timeFrame: Week 3
measure: Partial pathological response in Cohort 1
timeFrame: Week 6
measure: Partial pathological response in Cohort 2
timeFrame: Week 6
measure: Partial pathological response in Cohort 1
timeFrame: Week 9
measure: Partial pathological response in Cohort 2
timeFrame: Week 9
measure: Safety and tolerability of treatment - Cohort 1
timeFrame: Week 3
measure: Safety and tolerability of treatment - Cohort 2
timeFrame: Week 3
measure: Safety and tolerability of treatment - Cohort 1
timeFrame: Week 6
measure: Safety and tolerability of treatment - Cohort 2
timeFrame: Week 6
measure: Safety and tolerability of treatment - Cohort 1
timeFrame: Week 9
measure: Safety and tolerability of treatment - Cohort 2
timeFrame: Week 9
measure: Treatment success - Overall Survival in Cohort 1
timeFrame: 2 years after surgery.
measure: Treatment success - bladder recurrence and dissemination in Cohort 1
timeFrame: 2 years after surgery.
measure: Treatment success - Overall Survival in Cohort 2
timeFrame: 2 years after surgery.
measure: Treatment success - bladder recurrence and dissemination in Cohort 2
timeFrame: 2 years after surgery.
measure: Intercycle report : Blood cells & Platelets in Cohort 1
timeFrame: Week 3
measure: Intercycle report : Blood cells & Platelets in Cohort 2
timeFrame: Week 3
measure: Intercycle report : Electrolytes in Cohort 1
timeFrame: Week 3
measure: Intercycle report : Electrolytes in Cohort 2
timeFrame: Week 3
measure: Intercycle report : Liver in Cohort 1 - AST
timeFrame: Week 3
measure: Intercycle report : Liver in Cohort 1 - ALT
timeFrame: Week 3
measure: Intercycle report : Liver in Cohort 1 -GGT
timeFrame: Week 3
measure: Intercycle report : Liver in Cohort 1 - LDH
timeFrame: Week 3
measure: Intercycle report : Liver in Cohort 1 - ALP
timeFrame: Week 3
measure: Intercycle report : Liver in Cohort 1 - bilirubin
timeFrame: Week 3
measure: Intercycle report : Liver in Cohort 2 - AST
timeFrame: Week 3
measure: Intercycle report : Liver in Cohort 2 - ALT
timeFrame: Week 3
measure: Intercycle report : Liver in Cohort 2 - GGT
timeFrame: Week 3
measure: Intercycle report : Liver in Cohort 2 - LDH
timeFrame: Week 3
measure: Intercycle report : Liver in Cohort 2 - ALP
timeFrame: Week 3
measure: Intercycle report : Liver in Cohort 2 - bilirubin
timeFrame: Week 3
measure: Intercycle report : Creatinine Phosphokinase in Cohort 1
timeFrame: Week 3
measure: Intercycle report : Creatinine Phosphokinase in Cohort 2
timeFrame: Week 3
measure: Intercycle report : Thyroid in Cohort 1
timeFrame: Week 3
measure: Intercycle report : Thyroid in Cohort 2
timeFrame: Week 3
measure: Intercycle report : Cortisol in Cohort 1
timeFrame: Week 3
measure: Intercycle report : Cortisol in Cohort 2
timeFrame: Week 3
measure: Intercycle report : C-reactive protein in Cohort 1
timeFrame: Week 3
measure: Intercycle report : C-reactive protein in Cohort 2
timeFrame: Week 3
measure: Intercycle report : Urine in Cohort 1
timeFrame: Week 3
measure: Intercycle report : Urine in Cohort 2
timeFrame: Week 3
measure: Intercycle report: N-BNP, troponin in Cohort 1
timeFrame: Week 3
measure: Intercycle report: N-BNP, troponin in Cohort 2
timeFrame: Week 3
measure: Intercycle report: Blood cells & platelets in Cohort 1
timeFrame: Week 6
measure: Intercycle report: Blood cells & Platelets in Cohort 2
timeFrame: Week 6
measure: Intercycle report: Electrolytes in Cohort 1
timeFrame: Week 6
measure: Intercycle report : Electrolytes in Cohort 2
timeFrame: Week 6
measure: Intercycle report : Liver in Cohort 1 - AST
timeFrame: Week 6
measure: Intercycle report : Liver in Cohort 1 - ALT
timeFrame: Week 6
measure: Intercycle report : Liver in Cohort 1 - GGT
timeFrame: Week 6
measure: Intercycle report : Liver in Cohort 1 - LDH
timeFrame: Week 6
measure: Intercycle report : Liver in Cohort 1 - ALP
timeFrame: Week 6
measure: Intercycle report : Liver in Cohort 1 - bilirubin
timeFrame: Week 6
measure: Intercycle report : Liver in Cohort 2 - AST
timeFrame: Week 6
measure: Intercycle report : Liver in Cohort 2 - ALT
timeFrame: Week 6
measure: Intercycle report : Liver in Cohort 2 - GGT
timeFrame: Week 6
measure: Intercycle report : Liver in Cohort 2 - LDH
timeFrame: Week 6
measure: Intercycle report : Liver in Cohort 2 - ALP
timeFrame: Week 6
measure: Intercycle report : Liver in Cohort 2 - bilirubin
timeFrame: Week 6
measure: Intercycle report : Creatine Phosphokinase in Cohort 1
timeFrame: Week 6
measure: Intercycle report : Creatine Phosphokinase in Cohort 2
timeFrame: Week 6
measure: Intercycle report : Thyroid in Cohort 1
timeFrame: Week 6
measure: Intercycle report : Thyroid in Cohort 2
timeFrame: Week 6
measure: Intercycle report : Cortisol in Cohort 1
timeFrame: Week 6
measure: Intercycle report : Cortisol in Cohort 2
timeFrame: Week 6
measure: Intercycle report : C-reactive protein in Cohort 1
timeFrame: Week 6
measure: Intercycle report : C-reactive protein in Cohort 2
timeFrame: Week 6
measure: Intercycle report : Urine in Cohort 1
timeFrame: Week 6
measure: Intercycle report : Urine in Cohort 2
timeFrame: Week 6
measure: Intercycle report : N-BNP, troponin in Cohort 1
timeFrame: Week 6
measure: Intercycle report : N-BNP, troponin in Cohort 2
timeFrame: Week 6
measure: Intercycle report: Blood cells & Platelets in Cohort 1
timeFrame: Week 9
measure: Intercycle report: Blood cells & Platelets in Cohort 2
timeFrame: Week 9
measure: Intercycle report: Electrolytes in Cohort 1
timeFrame: Week 9
measure: Intercycle report: Electrolytes in Cohort 2
timeFrame: Week 9
measure: Intercycle report: Liver in Cohort 1
timeFrame: Week 9
measure: Intercycle report: Liver in Cohort 2
timeFrame: Week 9
measure: Intercycle report: Creatine Phosphokinase in Cohort 1
timeFrame: Week 9
measure: Intercycle report: Creatine Phosphokinase in Cohort 2
timeFrame: Week 9
measure: Intercycle report: Thyroid in Cohort 1
timeFrame: Week 9
measure: Intercycle report: Thyroid in Cohort 2
timeFrame: Week 9
measure: Intercycle report: Cortisol in Cohort 1
timeFrame: Week 9
measure: Intercycle report: Cortisol in Cohort 2
timeFrame: Week 9
measure: Intercycle report: C-reactive protein in Cohort 1
timeFrame: Week 9
measure: Intercycle report: C-reactive protein in Cohort 2
timeFrame: Week 9
measure: Intercycle report : Urine in Cohort 1
timeFrame: Week 9
measure: Intercycle report: Urine in Cohort 2
timeFrame: Week 9
measure: Intercycle report: N-BNP, troponin in Cohort 1
timeFrame: Week 9
measure: Intercycle report: N-BNP, troponin in Cohort 2
timeFrame: Week 9
Other outcomes:
measure: Tumor staging in Cohort 1
timeFrame: Just before surgery at weeks 14 to 18
measure: Tumor staging in Cohort 2
timeFrame: Just before surgery at weeks 14 to 18
measure: Results of biopsy on tissue specimens after surgery in Cohort 1
timeFrame: After surgery at weeks 14 to 18
measure: Results of biopsy on tissue specimens after surgery in Cohort 2
timeFrame: After surgery at weeks 14 to 18
measure: Overall survival in Cohort 1
timeFrame: Approximately two years after surgery
measure: Overall survival in Cohort 2
timeFrame: Approximately two years after surgery
measure: Bladder recurrence in Cohort 1
timeFrame: Approximately two years after surgery
measure: Bladder recurrence in Cohort 2
timeFrame: Approximately two years after surgery
measure: Dissemination in Cohort 1
timeFrame: Approximately two years after surgery
measure: Dissemination in Cohort 2
timeFrame: Approximately two years after surgery
Locations:
city: Paris
country: France
facility: Hôpital Bichat-Claude Bernard
state: Paris Cx 20
city: Marseille
country: France
facility: Institut Paoli Calmette
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Hôpital Pitié Salpétrière
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Pierre Bénite
country: France
facility: Centre hospitalier Lyon Sud
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Suresnes
country: France
facility: Hôpital Foch
city: Toulouse Cedex 9
country: France
facility: Iuct Oncopole
Study officials:
References: