Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

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

Recurrence

Non-Muscle Invasive Bladder Neoplasms

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Phase 1:

Induction: 6 intravesical instillations of VPM1002BC in 6-12 weeks (dose de-escalation in cohorts of 3-6 patients)

Phase 2:

Induction: VPM1002BC at RP2D established in phase I, 6 intravesical instillations in 6-12 weeks (n=39 including patients treated at RPD2 in phase I)

Maintenance: 3 instillations of VPM1002BC at months 3, 6 and 12

Phase 1:

Induction: 6 intravesical instillations of VPM1002BC in 6-12 weeks (dose de-escalation in cohorts of 3-6 patients)

Phase 2:

Induction: VPM1002BC at RP2D established in phase I, 6 intravesical instillations in 6-12 weeks (n=39 including patients treated at RPD2 in phase I)

VPM1002BC

Cyrill Rentsch, MD, PhD

Andreas Wicki, MD, PhD

This phase I/II trial will assess the safety and efficacy of intravesical instillation of VPM1002BC in patients with recurrent non-muscle invasive bladder cancer after TURB (transurethral resection of the bladder) and standard BCG therapy. In phase I part of the trial, a 3+3 dose de-escalation design will be applied to determine the recommended phase II dose (RP2D). In phase II part of the trial, a maximum of 39 patients will be treated at RP2D to further assess the preliminary efficacy of VPM1002BC.The efficacy and tolerability of VPM1002BC will be compared to results previously reported for BCG in a similar population. The quality of life will be also investigated as a secondary endpoint. Additional immunology assessments are foreseen as exploratory analyses to investigate the immunogenicity of VPM1002BC.

The Phase II of the trial has been opened on 27.07.2016.

Therapy background

For intermediate/high risk NMIBC clinical guidelines recommend as standard therapy complete transurethral resection of the bladder tumor (s) (TURB), followed by immunotherapy with six weekly intravesical instillations of approx. 5x10E8 CFUs of Bacillus Calmette Guérin (BCG) and maintenance BCG therapy for at least one year. In addition to the prevention of recurrences and progression of NMIBC, the use of BCG as a means of initiating anti-tumor immunity has been shown to prolong overall survival as compared to TURB alone. BCG has also been shown superior to intravesical chemotherapy in combination with BCG maintenance.

Worldwide, more than 200,000 patients are treated with BCG annually, 30-50% of which are likely to recur. While NMIBC incidence has increased over the past decades, death rates remain low due to the efficacy of intravesical BCG therapy. Failure to BCG therapy occurs in 40-50% of patients in terms of disease recurrence or progression. Due to the high risk of disease progression and to the lack of predictive markers for the risk of progression, radical cystectomy is the preferred option for patients failing to respond to a first course of standard BCG therapy, according to current guidelines.

However, a second course of BCG is appropriate for non high-grade and even for some high-grade recurrent tumors. Based on retrospective studies, a second induction course may achieve a 30% to 50% response rate in patients with an initial complete response and in patients with persistent carcinoma in situ (CIS) after a first course of BCG induction therapy. Only a few data are available from prospective studies regarding the outcome of a second BCG therapy cycle after BCG failure. Di Lorenzo et al (2010) reported on 40 patients receiving BCG reinduction: 87.5% of patients failed to respond to BCG re-induction at one year; one patient died of systemic disease, 37.5% of the patients had to undergo cystectomy and 40% underwent radiation therapy plus systemic chemotherapy after 1 year. Of note, these were initially patients unwilling or unfit to undergo cystectomy. In this trial, BCG reinduction was prospectively compared to intravesical chemotherapy with gemcitabine. The results indicated a small benefit for gemcitabine in terms of recurrence-free survival but no difference in terms of progression-free survival. The poor outcome in these patients failing to respond to BCG therapy reflects the unmet medical need for improved bladder sparing treatments after BCG or other intravesical treatment failure. We need better treatment options for patients failing to respond to BCG therapy as these patients are at high risk of cancer progression. Ultimately, improved treatment of these high-risk patients will increase bladder preservation rates and as a consequence, improve quality of life and decrease health costs.

Rationale for performing the trial

Despite the proven efficacy of BCG treatment in patients with NMIBC, recurrence-free and progression-free survival are still poor. Oddens and coworkers (2013) reported \~35-45% of patients recurred by 5 years and \~10-13% of patients progressed. Recurrence and progression to muscle invasive disease lead to additional surgical and radio-oncological interventions including transurethral resection of the bladder (TURB), cystectomy, and chemo-radiotherapy. Improvement in recurrence-free and progression-free survival rates in NMIBC, therefore, would lead to less surgery, better quality of life (QoL), and probably better overall survival.

For those patients failing to a first course of standard BCG therapy, current guidelines recommend radical cystectomy. Alternative options for patients include re-treatment with BCG or intravesical chemotherapy (including multimodal therapy). The earlier the BCG failure, the more probable is the failure of a second BCG cycle. Only few data are available regarding outcome of a second cycle of BCG after BCG failure. Rosevear (2011) reported a 66% complete response after BCG +IFN-α therapy after 6 months of therapy and Di Lorenzo (2010) reported an even worse 6-month recurrence-free survival (RFS) of \~62% (3% at 24 months). As such, better treatment options are not only needed for first line therapy but also for patients with recurrence after a first course of standard BCG therapy.

VPM1002BC is a live genetically modified Mycobacterium bovis BCG that was originally developed as a vaccine against tuberculosis.

VPM1002BC has an innovative mode of action with a unique potential of inducing tumor specific immune responses. VPM1002BC should be at least as potent as the currently used BCG strains in evoking immune responses. Moreover, based on preclinical data, a favourable adverse events profile is expected.

Therefore, the pivotal and final goal of this trial is the testing of VPM1002BC as a safe, well tolerated and efficacious treatment for NMIBC.

VPM1002BC will be tested for safety, efficacy, tolerability and immunogenicity in a phase I/II clinical trial, respectively, in patients with tumor recurrence after standard BCG according to EAU guidelines who are unwilling or unfit to undergo cystectomy. Thus, the reasons to choose this study population are based on the fact that this population has the highest need for innovative treatment and further to establish VPM1002BC as a safe and effective immunotherapy against NMIBC.

A phase I/II design was chosen in order to be able to assess safety and preliminary efficacy and tolerability of VPM1002BC. As the patient population qualifying for the trial is rare and the conventional BCG re-treatment has shown poor and very poor results (see above) we decided to use a single arm design and to compare efficacy and tolerability to reported results. Based on these conditions, the calculated sample size of 39-45 patients has resulted in a reasonable number of patients in terms of recruitment feasibility.

To the best of our knowledge VPM1002BC will be the first in man trial with recombinant intravesical bacteria and the first-in-man intra-bladder application of VPM1002BC.

Trial Treatment

VPM1002BC will be administered once per week as intravesical instillations as follows:

Induction:

- 6 instillations at weekly intervals. First instillation has to be done within 14 days after registration and corresponds to day 1 of the trial treatment schedule (= treatment start).

Maintenance:

* 3 instillations at weekly intervals starting at week 13 from day 1
* 3 instillations at weekly intervals starting at week 25 from day 1
* 3 instillations at weekly intervals starting at week 49 from day 1

Measurements and procedures:

Baseline assessments before trial therapy consist of radiological assessments, transurethral biopsy of the prostatic urethra in men (in case of suspected or previous CIS) followed by staged TUR of the prostate (in case of positive transurethral biopsy of the prostatic urethra ), PPD testing, TURB for histological confirmation of NMIBC (urothelial carcinoma) including second TURB for confirmation of tumor-free state except for pure CIS of the bladder, physical examination, ultrasound of bladder, blood testing for safety parameters, HIV, pregnancy test for women with child-bearing potential.

In phase I, induction therapy, for every weekly instillation: blood assessments for safety parameters (before the instillation and on day after the instillation), urine assessments (Nitrite, urine culture), urine cytology by bladder wash before instillation 1, vital signs (before the instillation and on day after the instillation). In addition, for instillations 1 and 6: assessment of excretion of VPM1002BC in blood, urine and sputum. In phase II, induction therapy, for instillations 1, 3 and 6 (before the instillation): blood assessments for safety parameters, urine assessments (Nitrite, urine culture). In addition, for instillation 1: physical examination including vital signs and weight, urine cytology by bladder wash.

During maintenance therapy (in phase I and II), for instillations 1 and 3 (before the instillation): blood assessments for safety parameters, urine assessments (Nitrite, urine culture). In addition, for each first instillation: physical examination and temperature.

At weeks 12, 24, 36, 48: cystoscopy, urine cytology by bladder wash, physical examination.

The following investigations have to be performed at the end of treatment (week 60): PPD testing, physical examination including vital signs and weight, blood assessments for safety parameters, urine assessments (Nitrite, urine cytology by bladder wash, urine culture), cystoscopy/cytology, abdominopelvic contrast enhanced CT scan.

Adverse events will be recorded continuously throughout the trial treatment. Treatment-related adverse events will be followed-up until resolution or stabilization.

Quality of Life will be assessed at baseline, before start of maintenance and at the end of trial treatment.

During the follow-up phase: survival status, recurrence and progression will be reported every 3 months in the first 2 years and thereafter every 6 months until 5 years.

VPM1002BC in Recurrent Non-muscle Invasive Bladder Cancer

A Phase I/II Open Label Clinical Trial Assessing Safety and Efficacy of Intravesical Instillation of VPM1002BC in Patients With Recurrent Non-muscle Invasive Bladder Cancer After Standard BCG Therapy

Adverse events grade 3 and 4 related to the trial treatment

No visual evidence of cancer in the bladder and negative cytology.

Progression is defined as a recurrence with an increased stage or grade.

from registration until 12 weeks after last instillation for patients not completing the overall treatment or after week 60 for patients completing the entire maintenance phase.

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
VPM1002BC in Recurrent Non-muscle Invasive Bladder Cancer	NCT02371447	Bladder Cancer	VPM1002BC	18 Years - 85 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

Spots Global Cancer Trial Database for vpm1002bc

Every month we try and update this database with for vpm1002bc cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for vpm1002bc

Every month we try and update this database with for vpm1002bc cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for vpm1002bc cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.