Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

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Urinary Bladder Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Gemcitabine

Cisplatin

Immunomodulating Agents

Atezolizumab

Immunoglobulins

BCG Vaccine

Adjuvants, Immunologic

Vaccines

Antimetabolites

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Immunologic Factors

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.

1 dose of VPM1002BC, live, 1-19.2 x 108 colony forming units (CFU) on day 1, 8 (+/- 1 day) and 15 (+/- 1 day)

Recombinant intravesical BCG (Bacillus Calmette-Guérin VPM1002BC)

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)

Sabrina Chiquet

Andreas Erdmann, MD

Frank Stenner, Prof

Ursula Vogl, MD

Martin Spahn, Prof

Richard Cathomas, MD

Petros Tsantoulis, MD

Christian Fankhauser, MD

Stefanie Aeppli, MD

Anja Lorch, Prof

Ulf Petrausch, MD

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.

Prospective single-arm open-label multicenter phase II trial

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

All AEs will be assessed according to NCI CTCAE v5.0. This endpoint will be calculated for patients in the safety set.

Swiss Group for Clinical Cancer Research

Symptoms and General Pathology

Rare Diseases

Carcinoma

Recurrence

Carcinoma, Transitional Cell

Transitional Cell Carcinoma

Anti-Infective Agents

Interferons

Interferon-alpha

Interferon alpha-2

Urine Collection and Bladder wash of Bladder Cancer Patients with Treatment of BCG or BCG plus interferon

Ashish M. Kamat, MD

The goal of this laboratory research study is to see if researchers can predict whose cancer will stay in remission and whose will return in patients receiving treatment for bladder cancer.

In this study, researchers are looking at markers that they could use to identify - at an early time point - those patients who might not respond to this treatment. This would allow researchers to provide future patients with information about their chances of responding to such treatment. And, with this information, researchers could better counsel those patients who might benefit from a different therapy at an earlier time point.

Treatment with BCG or BCG plus interferon is currently the most effective nonsurgical treatment for superficial bladder cancer. However, at this time, there is no reliable test that can help researchers predict which patients will respond to this therapy. You will be receiving BCG or BCG plus interferon therapy as planned by your physician. This is a standard therapy that will be decided by your doctor and based on your disease characteristics. If you agree to take part in this study, your participation will not affect the treatment you will receive in any way. Your follow-up and disease monitoring will be done according to standard routines.

By participating in this study, you agree to provide researchers with 4 tablespoons (or as much as you can produce) of urine at the following time points.

1. Before you start therapy.
2. Just before and 4 hours after your last treatment (which usually occurs 6 weeks after start of treatment).
3. Just before and 4 hours after your last treatment of the second course of therapy (which is usually about 3 months after the beginning of the first course of therapy.

In addition, you will provide researchers with a bladder wash sample. This sample will be collected during routine catheterization (for your planned treatment) or during your routine cystoscopic exam. Bladder wash samples will be collected at the following time points.

1. Before you start therapy.
2. Just before your last treatment (which usually occurs 6 weeks after start of treatment).
3. At your first routine cystoscopic follow-up (which usually occurs at 3 months).
4. At your second routine cystoscopic follow-up (which usually occurs at 6 months).

Your follow-up cystoscopies and maintenance therapy will be done according to routine care as decided by your doctor and are not affected by your participation in this study. You will be part of the study for about 24 months after beginning the treatments. At the end of that period, between 23 and 27 months, you will be checked with cystoscopy and cytology to see if the tumor has come back, as part of standard of care.

In addition, information will be collected from your medical chart about other medications that you are taking and other conditions, such as diabetes or heart disease, that you may have. Information will also be collected about previous treatment that you have had for bladder cancer as well as other treatments that you may receive during this study. This may include treatments that are received at an outside health facility. Neither your name nor your medical record number will be kept with this information. All of the information collected for this study will be kept in a locked cabinet to which only the researchers have access. Upon completion of the study, the information sheets will be destroyed.

This is an investigational study.

A total of 300 patients will take part in this study. All will be enrolled at MD Anderson.

4 tablespoons of urine and a bladder wash sample during catheterization (for planned treatment) or during routine cystoscopic exam, both samples at 4 different time points before, during and after therapy courses.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Intravesical Recombinant BCG Followed by Perioperative Chemo-immunotherapy for Patients With MIBC	NCT04630730	Bladder Cancer	Recombinant int... Atezolizumab Cisplatin Gemcitabine	18 Years -	Swiss Group for Clinical Cancer Research
Intravesical Recombinant BCG Followed by Perioperative Chemo-immunotherapy for Patients With MIBC	NCT04630730	Bladder Cancer	Recombinant int... Atezolizumab Cisplatin Gemcitabine	18 Years -	Swiss Group for Clinical Cancer Research
Markers of Response to Intravesical Bladder Cancer Therapy	NCT01007058	Bladder Cancer		18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for bacillus calmette guérin