1. Pathological complete remission (pCR) (Time Frame - At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start): 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.
Secondary outcome:
1. Event-free survival (EFS) (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): 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.
2. Recurrence-free survival (RFS) after R0 resection (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): 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.
3. Overall survival (OS) (Time Frame - From the date of treatment start until the date of death, assessed up to 5 years after surgery): 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.
4. Quality of resection: Complete resection (Time Frame - At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start): 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.
5. Quality of resection: Completeness of the lymphadenectomy and surgery (Time Frame - At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start): 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.
6. Quality of resection: Postoperative complications (Time Frame - At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start): 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.
7. Pathological response (PaR) rate (Time Frame - At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start): 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.
8. Pattern of recurrence (Time Frame - at the date of the first occurrence of recurrence, assessed up to 5 years after surgery): 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.
9. Treatment feasibility (Time Frame - from the date of treatment start until the date of treatment stop, estimated at approximately 63 to 79 weeks after treatment start): 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
10. Adverse events (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): All AEs will be assessed according to NCI CTCAE v5.0. This endpoint will be calculated for patients in the safety set.
Recombinant intravesical BCG (Bacillus Calmette-Guérin VPM1002BC) (VPM1002BC): 1 dose of VPM1002BC, live, 1-19.2 x 108 colony forming units (CFU) on day 1, 8 (+/- 1 day) and 15 (+/- 1 day)
Atezolizumab (Tecentriq™): Neoadjuvant immunotherapy with atezolizumab, 4 cycles 1200 mg fixed dose iv infusion on d1 q3w starting 4-16 weeks after date of surgery
Cisplatin (Platinol®): Neoadjuvant chemotherapy with cisplatin: 4 cycles 70mg/m2 iv infusion on d1 q3w (starting on d22)
Gemcitabine (Gemzar ®): Neoadjuvant chemotherapy with gemcitabine: 4 cycles 1000 mg/m2 iv infusion on d1 and d8 q3w (starting on d22)
Quelle: ClinicalTrials.gov
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"Intravesical Recombinant BCG Followed by Perioperative Chemo-immunotherapy for Patients With MIBC"
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