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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: Recombinant intravesical BCG (Bacillus Calmette-Guérin VPM1002BC)
* Drug: Atezolizumab
* Drug: Cisplatin
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent according to ICH/GCP regulations before registration and prior to any trial specific procedures Histologically proven urothelial cell carcinoma of the bladder (cT2, cT3 or cT4a and ≤ cN1 (defined as a solitary lymph node ≤ 2 cm in the greatest dimension) and cM0) and be considered suitable for curative multimodality treatment including radical cystectomy by a multidisciplinary tumor board All histological subtypes eligible with the exception of small cell component Age ≥ 18 years WHO performance status 0-1 Hematological function: hemoglobin ≥ 90 g/L, neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L Hepatic function: total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's disease ≤ 3.0 x ULN), AST ≤ 2.5 x ULN and ALT ≤ 2.5 x ULN, AP ≤ 2.5 x ULN Renal function: estimated glomerular filtration rate (eGFR) > 50 mL/min/1.73m², according to CKD-EPI formula Women of childbearing potential must use effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and until 5 months after the last dose of investigational drug Men agree not to donate sperm or to father a child during trial treatment and until 5 months after the last dose of investigational drug (www.swissmedicinfo.ch). Exclusion Criteria: Any pathological evidence of small-cell carcinoma component Presence of any distant metastasis History of hematologic or primary solid tumor malignancy, unless in remission for at least 3 years after registration, with the exception of adequately treated cervical carcinoma in situ, localized non-melanoma skin cancer or low risk localized prostate cancer (T1-T2a, Gleason <7, PSA <10ng/ml) Residual urinary bladder volume after micturition > 150ml (measured by ultrasound of bladder or inserted catheter) Prior treatment for bladder cancer including BCG instillations. Single dose intravesical chemotherapy instillation after TURB is allowed Bladder surgery or traumatic catheterization or TURB within 14 days prior to the expected start of BCG trial treatment Uncontrollable urinary tract infection, macroscopic haematuria, suspicion of bladder perforation, urethral strictures (if interfering with trial procedures) Any conditions preventing the patient from keeping BCG instillation in the bladder for at least 1 hour; anticholinergics are allowed to achieve this criterion Any previous treatment with a PD-1 or PD-L1 inhibitor, including atezolizumab Concomitant or prior use of immunosuppressive medication within 28 days before registration, with the exceptions of intranasal and inhaled corticosteroids, or systemic corticosteroids which must not exceed 10 mg/day of prednisone (or a dose equivalent corticosteroid) and the premedication for chemotherapy Concurrent treatment with other experimental drugs or other anticancer therapy, treatment in a clinical trial within 28 days prior to registration Major surgical procedure within 28 days prior to registration Preexisting peripheral neuropathy (> grade 1) Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: Patients with vitiligo or alopecia Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement Any chronic skin condition that does not require systemic therapy Patients without active disease in the last 5 years may be included but only after consultation with the Coordinating Investigator Patients with celiac disease controlled by diet alone Known history of human immunodeficiency virus (HIV) or active chronic Hepatitis C or Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (iv) antimicrobial treatment Known history of tuberculosis, known history of primary immunodeficiency, known history of allogeneic organ transplant, or receipt of live attenuated vaccine within 4 weeks prior to registration, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV), unstable angina pectoris, history of myocardial infarction within the last six months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia), significant QT-prolongation, uncontrolled hypertension Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information Known hypersensitivity to trial drugs or to any component of the trial drugs Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective single-arm open-label multicenter phase II trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Recombinant intravesical BCG<br>The Intravesical recombinant BCG (Bacillus Calmette-Guérin - VPM1002BC) is used as an immuno-stimulating agent. The patient will receive 3 weekly BCG instillations as induction treatment. 4 cycles of atezolizumab, a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1 inhibitor) will be administered in combination with the standard neoadjuvant chemotherapy cisplatin/gemcitabine. After surgery atezolizumab will be administered in the adjuvant setting for 13 cycles. | Drug: Recombinant intravesical BCG (Bacillus Calmette-Guérin VPM1002BC)<br>* 1 dose of VPM1002BC, live, 1-19.2 x 108 colony forming units (CFU) on day 1, 8 (+/- 1 day) and 15 (+/- 1 day)<br>* Other names: VPM1002BC;Drug: Atezolizumab<br>* Neoadjuvant immunotherapy with atezolizumab, 4 cycles 1200 mg fixed dose iv infusion on d1 q3w starting 4-16 weeks after date of surgery<br>* Other names: Tecentriq™;Drug: Cisplatin<br>* Neoadjuvant chemotherapy with cisplatin: 4 cycles 70mg/m2 iv infusion on d1 q3w (starting on d22)<br>* Other names: Platinol®;Drug: Gemcitabine<br>* Neoadjuvant chemotherapy with gemcitabine: 4 cycles 1000 mg/m2 iv infusion on d1 and d8 q3w (starting on d22)<br>* Other names: Gemzar ®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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 | 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. | from the date of registration until 28 days after the date of treatment stop, estimated at approximately 67 to 83 weeks after treatment start | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adjuvant, muscle-invasive bladder cancer, MIBC, intravesical BCG, Bacillus Calmette Guérin, VPM1002BC, atezolizumab, Cisplatin, Gemcitabine, neoadjuvant