Tumours of the urothelial tract requiring surgery (T1 high grade-T4a of the bladder, rare histological subtypes) and upper urinary tract (high grade or high risk) MedDRA version: 20.0 Level: LLT Classification code 10046384 Term: Ureteral cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10026426 Term: Malignant neoplasm of renal pelvis System Organ Class: 10029104 - Neoplasms benign, mal
Conditions
Interventions
Sponsors
Queen Mary University of London
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Willing and able to provide written informed consent 2. Ability to comply with the protocol 3. Age = 18 years 4. Residual disease after TURBT or ureteroscopy (surgical opinion, cystoscopy/ ureteroscopy or radiological evidence). 5. Fit and planned for cystectomy or radical surgery of the upper tract (according to local guidelines). 6. N0 or M0 disease CT or MRI (within 4 weeks of registration) 7. Representative formalin-fixed paraffin embedded (FFPE) tumour samples with an associated pathology report that are determined to be available and sufficient for central testing. 8. Patients who refuse neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant cisplatin-based therapy is not appropriate. 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 10. Negative pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential. 11. For female patients of childbearing potential to use a highly effecting form(s) of contraception (i.e. one that results in a low failure rate [ 2500/µL c. Lymphocyte count = 500/µL d. Platelet count = 100,000/µL (without transfusion within 2 weeks prior to Cycle 1, Day 1) e. Haemoglobin = 9.0 g/dL (patients may be transfused or receive erythropoietic treatment to meet this criterion). f. AST or ALT and alkaline phosphatase = 2.5 times the institutional upper limit of normal (ULN) and serum bilirubin level = 1.5 times the institutional ULN (patients with known Gilbert disease who have serum bilirubin level = 3 × the institutional ULN may be enrolled) g. INR and aPTT = 1.5 × the institutional ULN. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. h. Calculated creatinine clearance = 20 mL/min (Cockcroft-Gault formula) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 10 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 48
Exclusion criteria
Exclusion criteria: 1. Pregnant and lactating female patients. 2. Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis. 3. Previously intravenous chemotherapy for urothelial cancer. 4. Patients with prior allogeneic stem cell or solid organ transplantation. 5. Prior treatment with CD137 agonists, anti-CTLA-4, anti PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents. 6. Patients must not have had oral or IV steroids for 14 days prior to study entry. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed. 7. Received therapeutic oral or intravenous (IV) antibiotics within 14 days prior to enrolment (Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible). 8. Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study. 9. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment. 10. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment. 11. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease. 12. Malignancies other than Urothelial Carcinoma within 5 years prior to Cycle 1, Day 1. 13. Severe infections within 4 weeks prior to enrolment in the study. 14. Significant cardiovascular disease,. 15. History of idiopathic pulmonary fibrosis. 16. Patients with uncontrolled Type 1 diabetes mellitus. 17. Patients with active hepatitis infection. 18. Positive test for HIV. 19. Patients with active tuberculosis 20. History of gastrointestinal disorders which may interfere with the absorption of the study drug. 21. Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab. 22. History of autoimmune disease 23. Patients with a history of autoimmune-related hypothyroidism, unless on a stable dose of thyroid-replacement hormone. 24. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins 25. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine atezolizumab's ability to reduce the size of urothelial cancer in the bladder (rare histological subtypes) and upper urinary tract before surgery (measured as pathological complete response rate), and assess the impact of the drug on the body's immune system.;Secondary Objective: 1. Assess the safety and tolerability of atezolizumab in this patient population by collecting information about adverse events and surgical complications. 2. Assess the anti-tumour effect of atezolizumab by examining the radiological response (looking at pre- and posttreatment MRI/CT scan images), “disease free survival” rates, and overall patient survival.;Primary end point(s): This study has a clinical and a biological primary endpoint: Clinical: • Bladder Cohort rare histological subtypes: To assess the efficacy of atezolizumab pre-cystectomy with respect to pCR rate in patients with carcinoma of the urothelium of the bladder (T1 high grade-T4a) with mixed or rare histological subtypes • UTUC Cohort: To assess the efficacy of atezolizumab pre-surgery with respect to pCR rate in patients with high grade or high risk upper urinary tract urothelial carcinoma Biological: To assess the effect of 2 x 3 weekly cycles of atezolizumab pre-cystectomy on immune parameters in patients with T1 high grade-T4aN0M0 carcinoma of the bladder rare histological subtypes and before radical surgery for upper tract disease on immune parameters in patients with high risk upper urinary tract urothelial carcinoma;Timepoint(s) of evaluation of this end point: The primary endpoints (clinical and biological) will be analysed once at least 29 evaluable patients have had a cystectomy and have had their 4 week post-cystectomy visit for the bladder cohort. For the UTUC cohort, the primary endpoints (clinical and biological) will be analysed once at least 18 evaluable patients have had radical surgery and have had their 4 week post- radical surgery visit. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1)To evaluate the safety and tolerability of atezolizumab when given in the neoadjuvant setting before radical surgery in this population. 2) To assess the efficacy of atezolizumab given in the neoadjuvant setting before radical surgery with respect to anti-tumour effects as measured by Investigator assessed radiological response (RR). 3) To assess the efficacy of atezolizumab given in the neoadjuvant setting before radical surgery with respect to antitumour effects based on Investigator assessed disease-free survival (DFS). 4) To assess the efficacy of atezolizumab given in the neoadjuvant setting before radical surgery with respect to overall survival (OS).;Timepoint(s) of evaluation of this end point: 1) For the bladder cohort, the Trial Steering Committee will meet and review safety data after 10 patients and after the final patient have undergone radical surgery and completed their 4 week post-radical surgery visit. For the UTUC cohort, the Trial Steering Committee will meet and review safety data after 10 patients and after the final patient have undergone nephroureterectomy and completed their 4 week post-nephroureterectomy visit. The rest of the safety endpoint will be analysed at the end of the study. Adverse events are collected during treatment and up to 24 weeks post surgery. 2-4) Assessed at the end of the study. | — |
Countries
France, Spain, United Kingdom
Contacts
Public ContactClinical Operations Department
APICES SOLUCIONES S.L
Outcome results
None listed