VPM1002BC in Recurrent Non-muscle Invasive Bladder Cancer
Condition: Bladder Cancer
MeSH terms: Urinary Bladder Neoplasms; Non-Muscle Invasive Bladder Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): VPM1002BC
Intervention type(s): Drug
Intervention description(s): 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)
Other intervention name(s): Mycobacterium bovis BCG∆ureC::Hly+; VPM1002
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: bladder cancer; recurrent non-muscle invasive bladder cancer; VPM1002BC; BCG therapy