Urothelial cell carcinoma of the bladder Cancer
Conditions
Interventions
The study will examine two treatment routes (one for each route of administration – passive instillation and direct injection). These treatment routes are completely independent of each other and will
Sponsors
Sheffield Teaching Hospitals NHS Foundation Trust
Eligibility
Sex/Gender
All
Age
18 Years to 120 Years
Inclusion criteria
Inclusion criteria: 1. Patient must be fully informed about the study and have signed the informed consent form 2. Patients with mixed histologies are required to have predominant urothelial cell carcinoma in the bladder 3. Patients with pTis to T4N0 M0 for whom radical cystectomy is planned treatment for their urothelial cell carcinoma of the bladder. Radical cystectomy must be scheduled at least 6 weeks after confirmation of eligibility. This will include both MIBC and high-grade NMIBC tumours. 4. Patients with MIBC must be ineligible for cisplatin-based neo-adjuvant chemotherapy or have declined neoadjuvant chemotherapy 5. Aged 18 years old and over 6. Performance status: Eastern Co-operative Oncology Group (ECOG) 0-2 7. Patient must be willing and able to comply with the protocol, have mental capacity and (if a woman of childbearing potential [WOCBP]) use effective contraception throughout treatment and for 5 months after treatment completion 8. Have diagnostic biopsy tissue material (i.e., transurethral resection of bladder tumour [TURBT] sample) available for use in the trial 9. Adequate organ function within 28 days prior to confirmation of eligibility and 7 days of study treatment as defined below: 9.1. White blood cell count (WBC): >2X10^9/L 9.2. Lymphocyte count: = 0.5 x 10^9/L (= 500/µL) 9.3. Neutrophils: =1.5 X10^9/L 9.4. Platelets: =100 X10^9/L 9.5. Estimated glomerular filtration rate (eGFR): >30mL/min 9.6.Serum total bilirubin: <1.5 x upper limit of normal (ULN) OR =3 ULN in a patient with Gilbert’s Syndrome AND direct bilirubin =ULN 9.7.Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT): =1.5 x ULN 9.8.Haemoglobin: =90g/L 9.9.Urine dipstick: Negative for nitrites. (If positive then a negative MSU is required. If positive MSU then infection must be treated prior to starting treatment.)
Exclusion criteria
Exclusion criteria: 1. Active urinary tract infection in last 2 weeks prior to assessing eligibility. 2. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteraemia, or severe pneumonia, or any active infection that could impact patient safety. 3. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease (COPD) exacerbation) are eligible for the study. 4. Presence of indwelling urinary stent or history of vesico-ureteric reflux. 5. Other intravesical therapy within 2 weeks of assessing eligibility. 6. Prior radiotherapy to bladder or planned radiotherapy to bladder. 7. Reduced bladder capacity (defined as an inability to hold an intravesical instillation for 1 hour). 8. Positive pregnancy test (as eligibility assessment for WOCBP), breast-feeding women, patients intending to become pregnant during and within 5 months after last dose of atezolizumab, or patients unwilling to comply with contraception requirements. 9. Patients with active, known, or suspected autoimmune disease with the following exceptions: 9.1. Patients with vitiligo or alopecia; 9.2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement; 9.3. Any chronic skin condition that does not require systemic therapy; 9.4. Patients with coeliac disease controlled by diet alone; 9.5. Patients with Crohn’s disease or ulcerative colitis (must be inactive stable disease). 10. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumour necrosis factor-a [TNF-a] agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: 10.1. Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study. 10.2. Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or low dose corticosteroids for COPD or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study. 11. Positive test for hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV). 12. Patients considered a poor medical risk by the investigator due to a serious, uncontrolled medical disorder, non-malignant system disease or active uncontrolled infection. Examples include but are not limited to; active COVID-19 infection, any psychiatric disorder that prohibits obtaining informed consent or protocol compliance. 13. Prior systemic immune checkpoint inhibitor therapy (prior BCG is permitted). 14. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins. 15. Known hypersensitivity to Chinese hamster ovary cell products. 16. Prior allogeneic stem cell or solid organ transplantation. 17. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atez
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Dose confirmation stages: Number of DLTs observed during the DLT period for each dose confirmation stage. This will confirm the safety of passively instilled intravesical atezolizumab (single and multiple doses) and of atezolizumab (single and multiple doses) when injected directly into a tumour/bladder wall. DLTs will be defined as any of the following: 1. A treatment-related toxicity that delays the radical cystectomy (RC) by more than 2 weeks. 2. Grade 3 or higher haematuria. 3. Any grade 3 or higher immune-mediated toxicity. 4. Any serious adverse event (SAE) considered treatment-related 5. Grade 4 haematological or = grade 3 non-haematological toxicity that is considered treatment-related 6. Any other treatment-related event decided by the SRC to be clinically significant. DLTs will be assessed from day 1 of trial treatment (TT) until RC, or 4 weeks after the last dose if RC does not occur. Dose expansion stages: For the dose expansion stages, the primary endpoints are safety and toxicity, assessed by the occurrence of adverse events (AEs), adverse reactions (ARs), adverse events of special interest (AEoSIs), serious adverse events (SAEs), serious adverse reactions (SARs), suspected unexpected serious adverse reactions (SUSARs) and related unexpected serious adverse events (RUSAEs), graded according to NCI CTCAE Version 5.0. AEs and ARs: from day 1 of TT until 30 days post-RC (or planned RC if RC does not occur) or until initiation of new systemic anti-cancer treatment, whichever occurs first. RUSAEs: from RC until 30 days post-RC for participants undergoing RC only AEoSIs and SAEs: from day 1 of TT until 90 days post-RC (or planned RC if RC does not occur) or until initiation of new systemic anti-cancer treatment, whichever occurs first. SAEs will also be collected following informed consent but prior to initiation of TT, only if the SAE is caused by a protocol-mandated intervention SARs and SUSARs: from day 1 of TT until trial end | — |
Secondary
| Measure | Time frame |
|---|---|
| For both dose confirmation and dose-expansion stages: 1. Progression-free survival 2. Treatment compliance as assessed by dose omissions, dose delays, dose reductions, delays to RC and RC cancellations 3. Pathological complete response rate Progression-free survival will be assessed from the date of registration until 2 years post-¬registration of the final participant. Treatment compliance is collected from day 1 of trial treatment to the time of RC, or until the planned RC date in the event no surgery takes place. Pathological complete response is assessed using the local pathologist report following RC. For dose confirmation stages only: Safety and toxicity as assessed by the occurrence of AEs, ARs, AEoSIs, SAEs, SARs, SUSARs and RUSAEs graded according to NCI CTCAE Version 5.0. The timing of the safety and toxicity secondary endpoints is the same as the timing for the dose expansion safety and toxicity primary endpoint given “Primary outcome measure” above. | — |
Countries
England, United Kingdom
Contacts
Public ContactJamie Oughton
Outcome results
None listed