E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of patients with recurrent non-muscle invasive bladder cancer |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10005005 |
E.1.2 | Term | Bladder cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the efficacy, safety, tolerability and immunogenicity of intravesical VPM1002BC instillations in patients with recurrence of non-muscle-invasive bladder cancer (NMIBC) after TURB and standard BCG therapy. |
|
E.2.2 | Secondary objectives of the trial |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Disease characteristics:
-Histologically confirmed diagnosis of recurrent NMIBC (urothelial carcinoma) including repeat TURB confirming tumor-free state of the bladder (confirmed by TURB and biopsy) For patients with pure CIS of the bladder no repeat TURB is necessary.
-Negative cytology before start of treatment, except for patients with concomitant CIS.
-Planned treatment starts 2-6 weeks after last TURB
-Pathological grading includes reporting according to WHO 1973 and 2004.
-One previous cycle of intravesical BCG (induction phase with at least 5 instillations ± maintenance) not more than 5 years ago for NMIBC.
-Patients have recurrent high-risk NMIBC for progression (score 7-23), based on the European Organization for Research and Treatment of Cancer scoring system, failing BCG therapy (EAU 2008 definition), for whom radical cystectomy or re-induction with standard BCG is indicated. This includes:
o Patients with high-grade, non-muscle invasive tumor(s) present at both 3 and 6 months after start of the previous cycle of BCG therapy, and
o Any worsening of the disease under BCG treatment, such as a higher number of recurrences, higher tumor category or higher grade, or appearance of CIS, including low grade tumors, in spite of an initial response.
Patient characteristics:
-Patient must give written informed consent before registration.
-Baseline Quality of Life questionnaire has been completed.
-WHO performance status 0-2
-Age 18 - 85 years
-Adequate hematological values: WBC ≥2.5 x 109/L, platelets ≥ 100 x 109/L
-Adequate hepatic function: total bilirubin ≤ 2 x ULN, AST/ALT ≤ 5 x ULN
-Adequate renal function: eGFR ≥ 30 mL/min/1.73m2, no need for dialysis
-Women are not breastfeeding. Sexually active women must ensure that their partner wears a condom during intercourse. Women with child-bearing potential are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 6 months thereafter. A negative pregnancy test (serum or urine) before inclusion (within 7 days) into the trial is required for all women with child-bearing potential.
Sexually active men must use a condom during intercourse and ensure that his partner practices contraception. Men agree not to father a child during participation in the trial and during 6 months thereafter. |
|
E.4 | Principal exclusion criteria |
Disease characteristics:
-Current or previous ≥ T2 urothelial carcinoma (UC) of the urinary bladder
-Concomitant UC of upper urinary tract, prostate or urethra*, small cell carcinoma of the bladder (with or without neuroendocrine differentiation), micropapillary urothelial carcinoma, pure squamous cell carcinoma of the bladder, (UC with squamous differentiation is allowed), pure adenocarcinoma, lympho-vascular invasion (LVI) in the TURB specimen. * If a staged transurethral resection of the prostate (TURP) shows no histological evidence of UC in the deep resection layer of the prostate, the patient can be included.
-Previous or current evidence of UC in a bladder diverticulum
-Evidence of metastatic disease in the (thoraco-)abdominal CT scan at registration
-Bladder surgery or traumatic catheterization or TURB within 2 weeks prior to the expected start of trial treatment
-Administration of systemic cytotoxic agents within the past 3 years or administration of repeated cytostatic/cytotoxic drugs by intravesical instillations after a UC recurrence after the first BCG therapy (during the past 5 years). Exceptions are one immediate intravesical instillation (<24h) of a cytostatic/cytotoxic drug after TURB or repeated cytostatic/cytotoxic drugs by intravesical instillations before the first BCG therapy.
Patient characteristics:
-Stress urinary incontinence >I°, severe urge or urge urinary incontinence preventing the patient to keep the IMP in the bladder for at least 1 hour (anticholinergics and blocked catheter are allowed in order to achieve this criterion)
-Residual urinary bladder volume after micturition (measured by ultrasound of bladder or inserted catheter) is > 150 ml.
-Bladder diverticula or any other anatomical anomalies of the bladder that cannot be assessed by cystoscopy
-Active concomitant malignant conditions except basal cell skin carcinoma and cervical carcinoma in situ. History of malignancy in the last 3 years except previous NMIBC.
-Primary or secondary immunodeficiencies
-Positive HIV test
-Chronic administration (defined as more than 14 consecutive days) of immunosuppressive drugs or other immune modifying drugs within three months before instillation (for corticosteroids, this will mean prednisolone, or equivalent, 10mg/day). Inhaled and topical steroids are allowed.
-Uncontrollable urinary tract infection, macroscopic haematuria, suspicion of bladder perforation, urethral strictures (if interfering with trial procedures)
-Current and past pelvic radiation and brachytherapy
-Active tuberculosis, suspicion of active tuberculosis, other ongoing mycobacterial infection.
-Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction within the last three months, significant arrhythmias, significant QT-prolongation).
-History of anaphylaxis or severe allergic reactions, known allergies to any component of the investigational product, BCG intolerance
-Local and severe allergy (e.g. ulceration, systemic reactions) to PPD test
-Acute fever or fever (>38.5˚C) in the last 7 days before registration
-Simultaneous administration of antituberculous agents and antibiotics that cannot be stopped until registration
-Administration of immunoglobulins within the past 12 weeks
-Suspected or known current drug and/or alcohol abuse preventing compliance with trial treatment
-Patients who have participated in another clinical trial involving an investigational product within 30 days prior to trial entry
-Any on-going uncontrolled chronic illness (e.g. active autoimmune disease, uncontrolled diabetes)
-Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol and follow‐up.
-Psychiatric or neurological disorder precluding understanding of trial information, giving informed consent, filling out QoL forms |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the phase II part is:
-Recurrence-free rate in the bladder at 60 weeks. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Secondary endpoints of the trial are:
-Time to recurrence in the bladder
-Time to recurrence
-Time to progression
-Overall survival
-Adverse events
-Tolerability
-Quality of Life |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability and immunogenicity |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Germany |
Netherlands |
Switzerland |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 6 |