Brief Title
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
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.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Pathological complete response in Cohort 1
Secondary Outcome
Partial pathological response in Cohort 1
Condition
Urothelial Carcinoma
Intervention
Patients receiving neoadjuvant therapy before radical nephrectomy
Study Arms / Comparison Groups
Durvalumab+Gemcitabine/Cisplatin or with Gemcitabine/Carboplatin
Description: 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..
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
99
Start Date
September 29, 2021
Completion Date
October 1, 2025
Primary Completion Date
January 1, 2024
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.
- 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 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
- 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.
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
, +33 4 66 68 33 01, [email protected]
Location Countries
France
Location Countries
France
Administrative Informations
NCT ID
NCT04617756
Organization ID
CIVI/2018/NH-1
Responsible Party
Sponsor
Study Sponsor
Centre Hospitalier Universitaire de Nīmes
Collaborators
Pitié-Salpêtrière Hospital
Study Sponsor
, ,
Verification Date
December 2021