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
概览
- 阶段
- 2 期
- 干预措施
- Recombinant intravesical BCG (Bacillus Calmette-Guérin VPM1002BC)
- 疾病 / 适应症
- Bladder Cancer
- 发起方
- Swiss Cancer Institute
- 入组人数
- 46
- 试验地点
- 10
- 主要终点
- Pathological complete remission (pCR)
- 状态
- 进行中（未招募）
- 最后更新
- 3个月前
概览
简要总结
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.
详细描述
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.
研究者
入排标准
入选标准
- •Written informed consent according to ICH/GCP regulations before registration and prior to any trial specific procedures
- •Histologically proven urothelial cell carcinoma of the bladder (cT2, cT3 or cT4a and ≤ cN1 (defined as a solitary lymph node ≤ 2 cm in the greatest dimension) and cM0) and be considered suitable for curative multimodality treatment including radical cystectomy by a multidisciplinary tumor board
- •All histological subtypes eligible with the exception of small cell component
- •Age ≥ 18 years
- •WHO performance status 0-1
- •Hematological function: hemoglobin ≥ 90 g/L, neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L
- •Hepatic function: total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's disease ≤ 3.0 x ULN), AST ≤ 2.5 x ULN and ALT ≤ 2.5 x ULN, AP ≤ 2.5 x ULN
- •Renal function: estimated glomerular filtration rate (eGFR) \> 50 mL/min/1.73m², according to CKD-EPI formula
- •Women of childbearing potential must use effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and until 5 months after the last dose of investigational drug
- •Men agree not to donate sperm or to father a child during trial treatment and until 5 months after the last dose of investigational drug (www.swissmedicinfo.ch).
排除标准
- •Any pathological evidence of small-cell carcinoma component
- •Presence of any distant metastasis
- •History of hematologic or primary solid tumor malignancy, unless in remission for at least 3 years after registration, with the exception of adequately treated cervical carcinoma in situ, localized non-melanoma skin cancer or low risk localized prostate cancer (T1-T2a, Gleason \<7, PSA \<10ng/ml)
- •Residual urinary bladder volume after micturition \> 150ml (measured by ultrasound of bladder or inserted catheter)
- •Prior treatment for bladder cancer including BCG instillations. Single dose intravesical chemotherapy instillation after TURB is allowed
- •Bladder surgery or traumatic catheterization or TURB within 14 days prior to the expected start of BCG trial treatment
- •Uncontrollable urinary tract infection, macroscopic haematuria, suspicion of bladder perforation, urethral strictures (if interfering with trial procedures)
- •Any conditions preventing the patient from keeping BCG instillation in the bladder for at least 1 hour; anticholinergics are allowed to achieve this criterion
- •Any previous treatment with a PD-1 or PD-L1 inhibitor, including atezolizumab
- •Concomitant or prior use of immunosuppressive medication within 28 days before registration, with the exceptions of intranasal and inhaled corticosteroids, or systemic corticosteroids which must not exceed 10 mg/day of prednisone (or a dose equivalent corticosteroid) and the premedication for chemotherapy
研究组 & 干预措施
Recombinant intravesical BCG
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.
干预措施: Recombinant intravesical BCG (Bacillus Calmette-Guérin VPM1002BC)
Recombinant intravesical BCG
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.
干预措施: Atezolizumab
Recombinant intravesical BCG
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.
干预措施: Cisplatin
Recombinant intravesical BCG
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.
干预措施: Gemcitabine
结局指标
主要结局
Pathological complete remission (pCR)
时间窗: At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start
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.
次要结局
- Treatment feasibility(from the date of treatment start until the date of treatment stop, estimated at approximately 63 to 79 weeks after treatment start)
- Adverse events(from the date of registration until 28 days after the date of treatment stop, estimated at approximately 67 to 83 weeks after treatment start)
- Quality of resection: Completeness of the lymphadenectomy and surgery(At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start)
- Overall survival (OS)(From the date of treatment start until the date of death, assessed up to 5 years after surgery)
- Event-free survival (EFS)(From the date of treatment start until the date of progressive disease, recurrence of locoregional disease, appearance of metastases or death, whichever occurs first, assessed up to 5 years after surgery)
- Quality of resection: Complete resection(At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start)
- Quality of resection: Postoperative complications(At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start)
- Pattern of recurrence(at the date of the first occurrence of recurrence, assessed up to 5 years after surgery)
- Recurrence-free survival (RFS) after R0 resection(From the date of surgery until the date recurrence of locoregional disease, appearance of metastases or death, whichever occurs first, assessed up to 5 years after surgery)
- Pathological response (PaR) rate(At the date of tumor assessment after surgery, estimated at approximately 20 to 24 weeks after treatment start)