NCT04630730

Intravesical Recombinant BCG Followed by Perioperative Chemo-immunotherapy for Patients With MIBC

Intravesical Recombinant BCG (Bacillus Calmette Guérin) Followed by Perioperative Chemo-immunotherapy for Patients With Muscle-invasive Bladder Cancer (MIBC). A Multicenter, Single-arm Phase II Trial

• Status: Active Not Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 46 (estimated)
• Sponsor: Swiss Cancer Institute · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

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.

Conditions

• Bladder Cancer

Interventions

Type	Name	Description
DRUG	Recombinant intravesical BCG (Bacillus Calmette-Guérin 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)
DRUG	Atezolizumab	Neoadjuvant immunotherapy with atezolizumab, 4 cycles 1200 mg fixed dose iv infusion on d1 q3w starting 4-16 weeks after date of surgery
DRUG	Cisplatin	Neoadjuvant chemotherapy with cisplatin: 4 cycles 70mg/m2 iv infusion on d1 q3w (starting on d22)
DRUG	Gemcitabine	Neoadjuvant chemotherapy with gemcitabine: 4 cycles 1000 mg/m2 iv infusion on d1 and d8 q3w (starting on d22)

Timeline

• Start date: 2022-06-24
• Primary completion: 2026-06-01
• Completion: 2030-06-01
• First posted: 2020-11-16
• Last updated: 2026-01-21

Locations

10 sites across 1 country: Switzerland