A Prospective, Single Arm, Multicenter, Phase II-Trial to Assess Safety and Efficacy of Preoperative RAdiation Therapy Before Radical CystEctomy Combined With ImmunoTherapy in Locally Advanced Urothelial Carcinoma of the Bladder
Overview
- Phase
- Phase 2
- Intervention
- Nivolumab
- Conditions
- Urinary Bladder Cancer
- Sponsor
- Technical University of Munich
- Enrollment
- 33
- Locations
- 3
- Primary Endpoint
- Rate of patients with completed Treatment
- Last Updated
- 3 years ago
Overview
Brief Summary
A prospective, single arm, multicenter, Phase II-Trial to assess safety and efficacy of preoperative Radiation therapy before radical CystEctomy combined with ImmunoTherapy in locally advanced urothelial carcinoma of the bladder
Detailed Description
Patients with locally advanced bladder cancer have a poor prognosis despite radical surgical therapy. The addition of perioperative combination chemotherapy did not add significant benefit to surgery alone. There is data indicating a synergistic effect of radiation and immunotherapy. Therefore, combined application of radiotherapy with Nivolumab before radical cystectomy might lead to improved cure rates and local control in this poor prognosis group with locally advanced bladder cancer. The aim of this phase-II study is to assess feasibility and safety of immunotherapy combined with neoadjuvant radiation before radical cystectomy.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed, locally advanced bladder cancer (cT3/4 cN0/N+ cM0)
- •Urothelial cancer with at least 10% urothelial differentiation (excluding presence of small cell differentiation, which is not allowed in any percentage)
- •Histologic proof of muscle invasion in TUR-B specimen: ≥ pT2
- •Signs of locally advanced bladder cancer (at least one of the following must apply):
- •i. cT3/4 in imaging studies (bladder wall thickening or infiltration of perivesical fat/adjacent organs)
- •ii. Presence of hydronephrosis (or status post nephrostomy/ureteral stent due to hydronephrosis)
- •iii. Pelvic lymph nodes ≥ 8 mm in short axis
- •Ineligibility for neoadjuvant cisplatin-based chemotherapy due to any of the following criteria:
- •Creatinine Clearance (using the Cockcroft-Gault formula) \< 60 mL/min
- •Hearing loss ≥ grade 2 (CTCAE version 4)
Exclusion Criteria
- •Metastatic disease defined as distant metastasis or suspicious lymph nodes (\> 10mm short axis) outside the pelvis (clearly above aortic bifurcation) using RECIST 1.1 criteria. Enlarged lymph nodes in the pelvis below or at aortic bifurcation are NO exclusion criterion irrespective of size.
- •Prior chemotherapy before treatment (not including intravesical chemotherapy)
- •Prior radiation therapy of the pelvis
- •Active, known or suspected autoimmune disease (not including: vitiligo, allergic rhinitis/asthma, type 1 diabetes mellitus, residual hypothyroidism due to an autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger)
- •Immunosuppressive treatment with corticosteroids or other drugs within 14 days of study drug administration (not including: inhaled or topical steroids and adrenal replacement doses are permitted in the absence of active autoimmune disease)
- •Experimental therapy or clinical trial at time of inclusion or the previous 4 weeks
- •Previous treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways (not including BCG therapy)
- •Any uncontrolled or severe cardiovascular or pulmonary disease determined by the investigator, including i) NYHA functional classification III or IV, congestive heart failure, unstable or poorly controlled angina, uncontrolled hypertension, serious arrhythmia or myocardial infarction in previous 12 months before inclusion; ii) Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxic.
- •End-stage kidney disease defined as GFR \< 15ml/min or need for dialysis in absence of hydronephrosis. In case of hydronephrosis, drainage should be performed prior to inclusion preferably by nephrostomy, alternatively by ureteral stent placement.
- •Thromboembolic events like pulmonary embolism or apoplexy in previous 3 months
Arms & Interventions
Radio-Immunotherapy before cystectomy
Single arm treatment with Nivolumab during a neoadjuvant radiation therapy of the pelvis before radical cystectomy with standardized pelvic lymphadenectomy
Intervention: Nivolumab
Radio-Immunotherapy before cystectomy
Single arm treatment with Nivolumab during a neoadjuvant radiation therapy of the pelvis before radical cystectomy with standardized pelvic lymphadenectomy
Intervention: Radiation therapy of the pelvis
Radio-Immunotherapy before cystectomy
Single arm treatment with Nivolumab during a neoadjuvant radiation therapy of the pelvis before radical cystectomy with standardized pelvic lymphadenectomy
Intervention: Radical cystectomy with standardized pelvic lymphadenectomy
Outcomes
Primary Outcomes
Rate of patients with completed Treatment
Time Frame: end of week 15
Completed Treatment (consisting of radio-immunotherapy and radical cystectomy) is defined by Administration of at least 2 complete cycles of nivolumab 240 mg and Administration of at least 23 of planned 28 Radiation fractions (at least 41.4 Gy in total)
Secondary Outcomes
- Acute toxicity of preoperative radio-immunotherapy(beginning of treatment until 3 months after end of therapy)
- Rate of immune related toxicities(beginning of treatment until 12 months after cystectomy)
- Late toxicity(3 months after end of therapy until 12 months after cystectomy)
- Disease free survival(until 12 months after cystectomy)
- Overall survival(until 12 months after cystectomy)
- radiological Overall Response rate(after completion of radioimmunotherapy before cystectomy (week 12; range 11-14))
- ypT0 rate(after cystectomy was performed (week 16))
- surgical margin Status(after cystectomy was performed (week 16))