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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 39
- 试验地点
- 16
- 主要终点
- Phase 1: Dose limiting toxicity (DLT) of intravesical VPM1002BC instillations in patients with recurrence after standard BCG therapy in non-muscle-invasive bladder cancer.
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 2-5 weeks after last TURB
- •Pathological grading includes reporting according to WHO 1973 and
- •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.
排除标准
- •Current or previous ≥ T2 urothelial carcinoma (UC) of the urinary bladder
- •Bladder surgery or traumatic catheterization or TURB within 2 weeks prior to the expected start of trial treatment
- •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. Residual urinary bladder volume after micturition is > 150 ml.
- •Active concomitant malignant conditions except low risk prostate cancer qualifying for active surveillance according to PRIAS criteria (http://www.prostatecancer-riskcalculator.com/active-surveillance-and-prias-study), 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
- •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 or other ongoing mycobacterial infection.
- •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
研究组 & 干预措施
VPM1002BC Induction
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
干预措施: VPM1002BC (Drug)
结局指标
主要结局
Phase 1: Dose limiting toxicity (DLT) of intravesical VPM1002BC instillations in patients with recurrence after standard BCG therapy in non-muscle-invasive bladder cancer.
时间窗: within 5 weeks
Adverse events grade 3 and 4 related to the trial treatment
Phase 2: Recurrence-free rate in the bladder
时间窗: at 60 weeks
No visual evidence of cancer in the bladder and negative cytology.
次要结局
- Time to recurrence (from registration to recurrence at local, regional or distant site)(within 60 weeks)
- Time to recurrence in the bladder (from registration to tumor recurrence in the bladder)(within 60 weeks)
- Time to progression (from registration to progression).(within 60 weeks)
- Overall survival calculated from registration until death from any cause(from registration until death (within 6 years))
- Adverse events assessed according to NCI CTCAE v4.0.(within 60 weeks)
- Quality of Life assessed by questionnaires(within 60 weeks)