Current treatment of localized muscle-invasive bladder cancer is still associated with high relapse and death rate as well as the need for complete bladder resection or irradiation. The primary objective of this trial is to increase the rate of pathologic complete remission (pCR) at the time of radical cystectomy by the combination of local bladder instillation with Bacillus Calmette Guérin (BCG) in combination with systemic immunotherapy with atezolizumab and standard chemotherapy with cisplatin/gemcitabine. The trial tests the hypothesis whether BCG can enhance systemic and local immune response and thereby increase pCR rate and consequently also event-free survival. Improving pCR rate would be a next step to the ultimate goal of omitting radical surgery or extensive local radiotherapy to the bladder for these patients.
Current treatment of localized muscle-invasive bladder cancer is still associated with high relapse and death rate as well as the need for complete bladder resection or irradiation. In recent years, immunotherapy using PD-1 or PD-L1 immune checkpoint inhibitors (ICI) proved successful for patients with metastatic bladder cancer. The checkpoint inhibitors atezolizumab (anti PD-L1), pembrolizumab (anti PD-1) and nivolumab (anti PD-1) now represent the standard of care in the second line setting of metastatic bladder cancer and are all approved by Swissmedic for this indication. First results, in 2018, have been presented and published using immune checkpoint inhibitors as neoadjuvant treatment for localized muscle-invasive bladder cancer. SAKK has also performed a single arm phase II trial using neoadjuvant chemo-immunotherapy with cisplatin/gemcitabine in combination with the PD-L1 inhibitor durvalumab (SAKK 06/17). A preplanned interim analysis of the first 30 operated patients revealed a pCR rate of 30%. In this study, residual non-muscle invasive bladder cancer (NMIBC) was found in approximately 15% of cases. While these results are encouraging, the improvement of pCR rate compared to cisplatin-based chemotherapy alone is small and further improvement is needed. BCG induces an intense local inflammatory response that mediates tumor immunity. Several steps are involved in mounting the inflammatory response including attachment to the urothelium with uptake by antigen presenting cells (APC) and putative internalization into urothelial cells followed by a boost of the innate immune response and induction of adaptive responses. Based on these findings, intravesical BCG appears to be a very interesting agent to enhance the immune response and act as an adjuvant agent to increase anti-tumor response with immune checkpoint inhibition using monoclonal antibodies such as atezolizumab. The combination of intravesical BCG and systemic immune checkpoint inhibition is being studied for patients with non-muscle invasive bladder cancer in several ongoing phase III trials. the investigators therefore propose to add an induction cycle of intravesical recombinant BCG (VPM1002BC) (total of 3 weeks) to the backbone of neoadjuvant chemo-immunotherapy with cisplatin/gemcitabine and atezolizumab. The trial tests the hypothesis if recombinant BCG can enhance systemic and local immune response and thereby increase pCR rate and consequently also event-free survival. Improving pCR rate would be a next step to the ultimate goal of omitting radical surgery or extensive local radiotherapy to the bladder for these patients.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
46
1 dose of VPM1002BC, live, 1-19.2 x 108 colony forming units (CFU) on day 1, 8 (+/- 1 day) and 15 (+/- 1 day)
Neoadjuvant immunotherapy with atezolizumab, 4 cycles 1200 mg fixed dose iv infusion on d1 q3w starting 4-16 weeks after date of surgery
Neoadjuvant chemotherapy with cisplatin: 4 cycles 70mg/m2 iv infusion on d1 q3w (starting on d22)
Neoadjuvant chemotherapy with gemcitabine: 4 cycles 1000 mg/m2 iv infusion on d1 and d8 q3w (starting on d22)
Klinik Hirslanden - Onkozentrum Hirslanden
Zurich, Canton of Zurich, Switzerland
Kantonsspital Baden
Baden, Switzerland
Universitaetsspital Basel
Basel, Switzerland
Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli
Bellinzona, Switzerland
Lindenhofspital
Bern, Switzerland
Kantonsspital Graubuenden
Chur, Switzerland
Hôpitaux Universitaires Genève HUG
Geneva, Switzerland
Luzerner Kantonsspital
Lucerne, Switzerland
Kantonsspital St. Gallen
Sankt Gallen, Switzerland
UniversitaetsSpital Zuerich
Zurich, Switzerland
Pathological complete remission (pCR)
The primary endpoint of the trial is pCR after neoadjuvant treatment defined as ypT0ypN0 and no evidence of non-muscle invasive bladder cancer (low grade, high grade or CIS). The primary analysis will be based on the results from central pathology review.
Time frame: At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start
Event-free survival (EFS)
EFS is defined as the time from treatment start until one of the following events, whichever comes first: * Progression during neoadjuvant treatment leading to inoperability * Recurrence or progression (in case of disease persistence) of locoregional disease after surgery * Appearance of metastases at any localization * Death Patients without event at the time of analysis and patients starting a subsequent treatment in the absence of an event will be censored at the date of the last available assessment showing no event before the start of the subsequent treatment, if any. This endpoint will be calculated for patients in the FAS.
Time frame: From the date of treatment start until the date of progressive disease, recurrence of locoregional disease, appearance of metastases or death, whichever occurs first, assessed up to 5 years after surgery
Recurrence-free survival (RFS) after R0 resection
RFS after R0 resection is defined as the time from surgery until one of the following events, whichever comes first: * Recurrence of locoregional disease * Appearance of metastases at any localization * Death Patients without event at the time of analysis and patients starting a subsequent treatment in the absence of an event will be censored at the date of the last available assessment showing no event before the start of the subsequent treatment, if any. This endpoint will only be calculated for patients in the R0 resection set.
Time frame: From the date of surgery until the date recurrence of locoregional disease, appearance of metastases or death, whichever occurs first, assessed up to 5 years after surgery
Overall survival (OS)
OS is defined as the time from treatment start until death from any cause. Patients not experiencing an event will be censored at the last date they were known to be alive. This endpoint will be calculated for patients in the FAS.
Time frame: From the date of treatment start until the date of death, assessed up to 5 years after surgery
Quality of resection: Complete resection
The quality of resection will be assessed in the following way: • Complete resection (R0) defined as free resection margins proved microscopically This endpoint will only be calculated for patients in the resected patients set.
Time frame: At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start
Quality of resection: Completeness of the lymphadenectomy and surgery
The quality of resection will be assessed in the following way: • Completeness of the lymphadenectomy and surgery using the photo documentation and histopathology This endpoint will only be calculated for patients in the resected patients set.
Time frame: At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start
Quality of resection: Postoperative complications
The quality of resection will be assessed in the following way: • Postoperative complications will be assessed using the Clavien-Dindo classification. This endpoint will only be calculated for patients in the resected patients set.
Time frame: At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start
Pathological response (PaR) rate
PaR rate is defined as pathological downstaging to ≤ ypT1N0M0. The proportion of patients with PaR will be calculated for patients in the resected patients set. This endpoint will only be calculated for patients in the resected patients set.
Time frame: At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start
Pattern of recurrence
Pattern of recurrence is defined as location of first tumor recurrence. Patterns can be locoregional or distant or any combination of these patterns. Patients with secondary malignancies or patients with no recurrence will not be taken into consideration for this endpoint.
Time frame: at the date of the first occurrence of recurrence, assessed up to 5 years after surgery
Treatment feasibility
The following feasibility criteria will be assessed: * Completion of 3 instillations of intravesical VPM1002BC * Completion of 4 cycles of neoadjuvant chemotherapy * Completion of 4 cycles of neoadjuvant atezolizumab treatment * Timely admission to and completion of planned surgery * Timely initiation and completion of 13 cycles of adjuvant atezolizumab treatment
Time frame: from the date of treatment start until the date of treatment stop, estimated at approximately 63 to 79 weeks after treatment start
Adverse events
All AEs will be assessed according to NCI CTCAE v5.0. This endpoint will be calculated for patients in the safety set.
Time frame: from the date of registration until 28 days after the date of treatment stop, estimated at approximately 67 to 83 weeks after treatment start
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