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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 50
- 试验地点
- 9
- 主要终点
- Pathological complete response in Cohort 2
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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
- •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.
排除标准
- •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.
研究组 & 干预措施
Durvalumab+Gemcitabine/Cisplatin or with Gemcitabine/Carboplatin
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..
干预措施: Patients receiving neoadjuvant therapy before radical nephrectomy (Drug)
结局指标
主要结局
Pathological complete response in Cohort 2
时间窗: Week 14 - 18
For Cohort 2 (patients on treatment combining Durvalumab and Gemcitabine associated with Carboplatin) the rate of patients with pathological complete response will be calculated and presented with associated 95% confidence interval on the subpopulation of patients with ureteroscopic biopsy at diagnosis.Pathological complete response is defined as no residual signs of viable tumor cells in tissue samples removed during surgery after treatment. 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.
Pathological complete response in Cohort 1
时间窗: Week 14 - 18
For Cohort 1 (patients on treatment combining Durvalumab and Gemcitabine associated with Cisplatin) the rate of patients with pathological complete response will be calculated and presented with associated 95% confidence interval on the subpopulation of patients with ureteroscopic biopsy at diagnosis.Pathological complete response is defined as no residual signs of viable tumor cells in tissue samples removed during surgery after treatment. 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.
次要结局
- Safety and tolerability of treatment - Cohort 2(Week 9)
- Treatment success - Overall Survival in Cohort 1(2 years after surgery.)
- Treatment success - bladder recurrence and dissemination in Cohort 2(2 years after surgery.)
- Intercycle report : Liver in Cohort 1 -GGT(Week 3)
- Intercycle report : Liver in Cohort 1 - LDH(Week 6)
- Intercycle report : Liver in Cohort 1 - bilirubin(Week 6)
- Intercycle report : Liver in Cohort 2 - ALT(Week 6)
- Intercycle report : Liver in Cohort 2 - bilirubin(Week 6)
- Safety and tolerability of treatment - Cohort 1(Week 9)
- Treatment success - Overall Survival in Cohort 2(2 years after surgery.)
- Intercycle report : Liver in Cohort 1 - ALT(Week 6)
- Intercycle report : Liver in Cohort 1 - ALP(Week 6)
- Intercycle report : Liver in Cohort 2 - GGT(Week 6)
- Intercycle report : Cortisol in Cohort 1(Week 6)
- Partial pathological response in Cohort 1(Week 9)
- Partial pathological response in Cohort 2(Week 9)
- Intercycle report : Electrolytes in Cohort 1(Week 3)
- Treatment success - bladder recurrence and dissemination in Cohort 1(2 years after surgery.)
- Intercycle report : Electrolytes in Cohort 2(Week 6)
- Intercycle report : Liver in Cohort 2 - LDH(Week 6)
- Intercycle report : Liver in Cohort 2 - ALP(Week 6)
- Intercycle report : Thyroid in Cohort 1(Week 6)
- Intercycle report : Thyroid in Cohort 2(Week 6)
- Intercycle report: Electrolytes in Cohort 1(Week 9)
- Intercycle report : Creatine Phosphokinase in Cohort 2(Week 6)
- Intercycle report : Blood cells & Platelets in Cohort 1(Week 3)
- Intercycle report: N-BNP, troponin in Cohort 1(Week 9)
- Intercycle report : Liver in Cohort 1 - GGT(Week 6)
- Intercycle report: Blood cells & Platelets in Cohort 1(Week 9)
- Intercycle report: Creatine Phosphokinase in Cohort 2(Week 9)
- Intercycle report: Thyroid in Cohort 2(Week 9)
- Intercycle report : Blood cells & Platelets in Cohort 2(Week 3)
- Intercycle report : Liver in Cohort 1 - AST(Week 6)
- Intercycle report : Liver in Cohort 2 - AST(Week 6)
- Intercycle report : Creatinine Phosphokinase in Cohort 1(Week 3)
- Intercycle report : Creatinine Phosphokinase in Cohort 2(Week 3)
- Intercycle report : C-reactive protein in Cohort 1(Week 6)
- Intercycle report : C-reactive protein in Cohort 2(Week 6)
- Intercycle report: Blood cells & Platelets in Cohort 2(Week 9)
- Intercycle report : Creatine Phosphokinase in Cohort 1(Week 6)
- Intercycle report : N-BNP, troponin in Cohort 1(Week 6)
- Intercycle report : Cortisol in Cohort 2(Week 6)
- Intercycle report : Urine in Cohort 1(Week 9)
- Intercycle report: N-BNP, troponin in Cohort 2(Week 9)
- Intercycle report: C-reactive protein in Cohort 2(Week 9)
- Intercycle report : Urine in Cohort 2(Week 6)
- Intercycle report: Blood cells & platelets in Cohort 1(Week 6)
- Intercycle report : N-BNP, troponin in Cohort 2(Week 6)
- Intercycle report: Electrolytes in Cohort 2(Week 9)
- Intercycle report: C-reactive protein in Cohort 1(Week 9)
- Intercycle report: Urine in Cohort 2(Week 9)
- Intercycle report: Liver in Cohort 1(Week 9)
- Intercycle report: Liver in Cohort 2(Week 9)
- Intercycle report: Creatine Phosphokinase in Cohort 1(Week 9)
- Intercycle report: Thyroid in Cohort 1(Week 9)
- Intercycle report: Cortisol in Cohort 1(Week 9)
- Intercycle report: Cortisol in Cohort 2(Week 9)