The study will evaluate the safety and efficacy of a combined therapy consisting of immuntherapy and radiation prior to radical cystectomy in patients with locally advanced urothelial bladder cancer

Phase 1

• Conditions: ocally advanced urothelial bladder cancer; MedDRA version: 20.0Level: PTClassification code 10005003Term: Bladder cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2018-001823-38-DE
• Lead Sponsor: Technische Universität München, Fakultät für Medizin vertreten durch den Dekan

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2018-06-27
• Last Update Posted: 5 April 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 33

Inclusion Criteria

- Histologically confirmed, locally advanced bladder cancer (cT3/4 cN0/N+ cM0)
o Urothelial cancer with at least 10% urothelial differentiation (excluding presence of small cell differentiation, which is not allowed in any
percentage)
o Histologic proof of muscle invasion in TUR-B specimen: = pT2
o Signs of locally advanced bladder cancer (at least one of the following must apply):
-- cT3/4 in imaging studies (bladder wall thickening or infiltration of perivesical fat/adjacent organs)
-- Presence of hydronephrosis (or status post nephrostomy/ureteral stent due to hydronephrosis)
-- Pelvic lymph nodes = 8 mm in short axis
-Ineligibility for neoadjuvant cisplatin-based chemotherapy due to any of the following criteria:
oCreatinine Clearance (using the Cockcroft-Gault formula) < 60 mL/min
oHearing loss = grade 2 (CTCAE version 4)
oPeripheral neuropathy = grade 2 (CTCAE version 4)
oECOG performance score 2
oHeart Failure NYHA Class III or IV
-Subjects that are eligible for cisplatin may be candidates if they refuse available neoadjuvant cisplatin-based chemotherapy, despite being informed by the investigator about the treatment options. The subject’s refusal must be thoroughly documented.
- Eligible for radical cystectomy
- ECOG 0 - 2
- Estimated life expectancy > 6 months
- Adequate function of bone marrow, liver and kidney:
o WBC = 2000/µL
o Neutrophils = 1500/µL
o Platelets = 100 × 103/µL
o Hemoglobin = 9.0 g/dL
o AST = 3 × ULN
o ALT = 3 × ULN
o Total bilirubin = 1.5 × ULN (except in participants with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
o GFR = 15 mL/min without hydronephrosis. In case of hydronephrosis, drainage should be performed prior to inclusion preferably by nephrostomy,
alternatively by ureteral stent placement. Use measured creatinine-clearance or estimated clearance (Cockcroft-Gault formula):
Female CrCl = [(140 - age in years) × weight in kg × 0.85] / [72 x serum creatinine in mg/dL]
Male CrCl = [(140 - age in years) × weight in kg × 1.00] / [72 x serum creatinine in mg/dL]
- Informed consent:
o Participants must have signed and dated an IEC approved written informed consent form in accordance with regulatory and institutional
guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal participant care.
o Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study
- Body weight 35 kg - 160 kg
- Female patients with childbearing potential must have a negative serum pregnancy test prior to start of trial.
- Women of childbearing potential (WOCBP) and men (who are sexually active with WOCBP) must use any contraceptive method with a failure rate of
less than 1% per year (see Appendix 15.7). These patients will be instructed to adhere to contraception for the period between the inclusion into study and surgery (which leads to sterility). Women who are not of childbearing potential (i.e. who are postmenopausal or surgically sterile)
as well as sterile men do not require contraception. If patients do not undergo surgery or in the rare case of fertility preserving cystectomy , effective contraception should be used for at least 5 months following the last dose of Nivolumab. In the latter instance serum pregnancy testing is required in WOCBP at the end o

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) within 5 years before study inclusion
- 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
- Other active tumor disease (not including basal cell carcinoma of the skin, carcinoma in situ of the cervix and incidental prostate carcinoma). Tumor is
regarded non active after curative therapy and 5 years of follow up without pathological findings.
- Medium to extended surgery or trauma in the previous 4 weeks (not including transurethral bladder resection, nephrostomy or ureteral stent or
biopsy)
- Uncontrolled and serious somatic or mental illness
- Age < 18 years
- Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.
- Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities [§ 40 Abs. 1 S. 3 Nr. 4 AMG].
- Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot
form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
- Female subjects who are pregnant, breast-feeding or male/female patients of childbearing potential who are not employing an effective method of
birth control (failure rate of less than 1% per year). [Acceptable methods of contraception are: implants, injectable contraceptives, combined oral
contraceptives, intrauterine p

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified