Phase II Trial of Intravesical Gemcitabine and MK-3475 (Pembrolizumab) in the Treatment of Patients With BCG-Unresponsive Non-Muscle Invasive Bladder Cancer
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 161
- 试验地点
- 664
- 主要终点
- Complete response rate in the carcinoma in situ (CIS) subpopulation
研究概览
简要总结
This phase II trial studies the effect of adding pembrolizumab to gemcitabine in treating patients with non-muscle invasive bladder cancer whose cancer does not respond to Bacillus Calmette-Guerin (BCG) treatment. Chemotherapy drugs, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the patient's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Adding pembrolizumab to gemcitabine may delay the return of BCG-unresponsive bladder cancer for longer period compared to gemcitabine alone.
详细描述
PRIMARY OBJECTIVES:
I. Estimate the 6-month complete response rate of treatment with intravesical gemcitabine hydrochloride (gemcitabine) in combination with MK-3475 (pembrolizumab) in patients with Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) that have a carcinoma in situ (CIS) component.
II. Estimate the 18 month event-free survival (EFS) rate for all patients with BCG-unresponsive NMIBC receiving intravesical gemcitabine in combination with MK-3475 (pembrolizumab).
SECONDARY OBJECTIVES:
I. To characterize the safety profile of the combination of intravesical gemcitabine with MK-3475 (pembrolizumab) with BCG-unresponsive NMIBC (CIS or high grade Ta and T1 with or without a CIS component).
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •High grade Ta, T1 or CIS urothelial carcinoma. Accrual of patients with Ta or T1 disease may be closed to ensure adequate patients enrollment to meet the primary endpoint
- •Persistent disease (defined as not achieving disease free status) after completing therapy with at least induction BCG (>= 5 doses) and the first round of maintenance or second induction course (>= 2 doses). The subsequent round of BCG, either maintenance or repeat induction, must be given within 6 months of initial induction BCG
- •Persistent high risk NMIBC (T1, high grade Ta and/or CIS) must be within 9 months of the last BCG instillation despite having received adequate BCG as defined above.
- •Registration must be within 12 months of last BCG instillation
- •High grade T1 after completing therapy with at least induction BCG (>= 5 doses) or after completing therapy with at least induction BCG (>= 5 doses) and first round of maintenance or second induction course (>= 2 doses). The subsequent round of BCG, either maintenance or repeat induction, must be given within 6 months of initial induction BCG
- •Disease recurrence (T1) must be within 9 months of the last BCG instillation despite having received adequate BCG as defined above
- •Registration must be within 12 months of last BCG instillation
- •Mixed variant histology (adenocarcinoma, squamous cell carcinoma) is eligible, but pure variant histology is ineligible
- •Patients who are disease free at 6 months after starting BCG but have high grade recurrence (T1, Ta, CIS) while on maintenance therapy would be eligible
- •The recurrence must be within 6 months of the last BCG dose.
- •Registration must be within 12 months of last maintenance BCG instillation
- •Patients must be deemed unfit for radical cystectomy by the treating physician or refuse radical cystectomy
- •All patients must have histologically confirmed urothelial cancer of the bladder within 60 days prior to registration
- •All visible tumor must be completely resected 60 days prior to registration (residual pure CIS is permitted)
- •All patients must have had a cystoscopy (or TURBT with complete resection) without papillary tumor and negative urinary cytology within 28 days of registration (positive cytology is allowed in patients with CIS)
- •All patients with T1 tumors must undergo a re-staging transurethral resection of bladder tumor (TURBT) within 60 days of registration
- •There must be uninvolved muscularis propria present in the re-staging TURBT. The initial TURBT prior to re-staging TURBT may be greater than 60 days prior to registration
- •Patients must have had imaging with CT or MRI abdomen/pelvis within 90 days of registration demonstrating no evidence of metastasis
- •Patients cannot have had a history of urothelial carcinoma in the ureters or prostatic urethra 24 months prior to registration
- •Patients must not be currently participating in or have participated in a study of an investigational agent or have used an investigational device within 4 weeks prior to study registration
- •Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been more than 4 weeks after the last dose of the previous investigational agent at time of registration
- •Patients must not have prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137)
- •Patients must not have undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years prior to registration. (Participants who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of graft versus host disease [GVHD])
- •Patients must not have received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to treatment
- •Note: Participants must have recovered from all adverse events (AEs) due to previous therapies to =< grade 1 or baseline. Participants with =< grade 2 neuropathy may be eligible
- •Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
- •Patients must not have received prior radiotherapy within 2 weeks of study registration. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
- •Patients must not have received radiation therapy to the lung that is > 30 Gy within 6 months prior to trial registration
- •Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects
- •Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Include as applicable: Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom)
- •A woman of childbearing potential (WOCBP) must not have a positive urine pregnancy test within 7 days prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- •Patients must not be pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with registration through the last dose of treatment
- •Age >= 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •Absolute neutrophil count (ANC) >= 1,500/mm^3
- •Platelet count >= 100,000/mm^3
- •Hemoglobin >= 9.0 g/dL
- •Creatinine =< 1.5 x upper limit of normal (ULN)
- •In patients with creatinine > 1.5 x ULN, if measured or calculated creatinine clearance > 30 mL/min, then patient is eligible
- •Total bilirubin =< 1.5 x ULN
- •In patients with a total bilirubin > 1.5 x ULN, if direct bilirubin < 1.0 X ULN, then patient is eligible
- •Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) =< 2.5 x ULN
- •Patients must not have had an active autoimmune disease requiring systemic treatment within 24 months prior to registration. Autoimmune diseases include, but not limited to, lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis
- •Patients must not have a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to registration
- •Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
- •Patients must not have a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
- •Patients must not have active tuberculosis
- •Patients must not have been treated with antibiotics for an active infection within 14 days prior to registration. Prophylactic antibiotics are permitted. Treatment for a urinary tract infection (UTI) is allowed but must be deemed adequately treated by the treating physician prior the start of cycle 1 (C1) day 1 (D1)
- •Patients must not have a history of idiopathic pulmonary fibrosis or organizing pneumonia
- •Patients must not have a history of (non-infectious) pneumonitis that required steroids or have current pneumonitis
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排除标准
- 未提供
研究组 & 干预措施
Treatment (pembrolizumab, gemcitabine hydrochloride)
INDUCTION: Patients receive pembrolizumab IV over 25-40 minutes on day 1 of cycles 1-4. Patients also receive gemcitabine hydrochloride intravesically on days 1, 8 and 15 of cycles 1 and 2. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Beginning cycle 5, patients with no evidence of disease after induction receive pembrolizumab IV over 25-40 minutes and gemcitabine intravesically on day 1 of each cycle. Treatment repeats every 3 weeks for 12 cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients with T1 tumors undergo a re-staging TURBT within 60 days of registration. Patients also undergo urine and blood sample collection, bladder biopsy, cystoscopy, CT and MRI throughout the study.
干预措施: Biospecimen Collection (Procedure)
Treatment (pembrolizumab, gemcitabine hydrochloride)
INDUCTION: Patients receive pembrolizumab IV over 25-40 minutes on day 1 of cycles 1-4. Patients also receive gemcitabine hydrochloride intravesically on days 1, 8 and 15 of cycles 1 and 2. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Beginning cycle 5, patients with no evidence of disease after induction receive pembrolizumab IV over 25-40 minutes and gemcitabine intravesically on day 1 of each cycle. Treatment repeats every 3 weeks for 12 cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients with T1 tumors undergo a re-staging TURBT within 60 days of registration. Patients also undergo urine and blood sample collection, bladder biopsy, cystoscopy, CT and MRI throughout the study.
干预措施: Computed Tomography (Procedure)
Treatment (pembrolizumab, gemcitabine hydrochloride)
INDUCTION: Patients receive pembrolizumab IV over 25-40 minutes on day 1 of cycles 1-4. Patients also receive gemcitabine hydrochloride intravesically on days 1, 8 and 15 of cycles 1 and 2. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Beginning cycle 5, patients with no evidence of disease after induction receive pembrolizumab IV over 25-40 minutes and gemcitabine intravesically on day 1 of each cycle. Treatment repeats every 3 weeks for 12 cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients with T1 tumors undergo a re-staging TURBT within 60 days of registration. Patients also undergo urine and blood sample collection, bladder biopsy, cystoscopy, CT and MRI throughout the study.
干预措施: Pembrolizumab (Biological)
Treatment (pembrolizumab, gemcitabine hydrochloride)
INDUCTION: Patients receive pembrolizumab IV over 25-40 minutes on day 1 of cycles 1-4. Patients also receive gemcitabine hydrochloride intravesically on days 1, 8 and 15 of cycles 1 and 2. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Beginning cycle 5, patients with no evidence of disease after induction receive pembrolizumab IV over 25-40 minutes and gemcitabine intravesically on day 1 of each cycle. Treatment repeats every 3 weeks for 12 cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients with T1 tumors undergo a re-staging TURBT within 60 days of registration. Patients also undergo urine and blood sample collection, bladder biopsy, cystoscopy, CT and MRI throughout the study.
干预措施: Cystoscopy (Procedure)
Treatment (pembrolizumab, gemcitabine hydrochloride)
INDUCTION: Patients receive pembrolizumab IV over 25-40 minutes on day 1 of cycles 1-4. Patients also receive gemcitabine hydrochloride intravesically on days 1, 8 and 15 of cycles 1 and 2. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Beginning cycle 5, patients with no evidence of disease after induction receive pembrolizumab IV over 25-40 minutes and gemcitabine intravesically on day 1 of each cycle. Treatment repeats every 3 weeks for 12 cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients with T1 tumors undergo a re-staging TURBT within 60 days of registration. Patients also undergo urine and blood sample collection, bladder biopsy, cystoscopy, CT and MRI throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Treatment (pembrolizumab, gemcitabine hydrochloride)
INDUCTION: Patients receive pembrolizumab IV over 25-40 minutes on day 1 of cycles 1-4. Patients also receive gemcitabine hydrochloride intravesically on days 1, 8 and 15 of cycles 1 and 2. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Beginning cycle 5, patients with no evidence of disease after induction receive pembrolizumab IV over 25-40 minutes and gemcitabine intravesically on day 1 of each cycle. Treatment repeats every 3 weeks for 12 cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients with T1 tumors undergo a re-staging TURBT within 60 days of registration. Patients also undergo urine and blood sample collection, bladder biopsy, cystoscopy, CT and MRI throughout the study.
干预措施: Transurethral Resection of Bladder Tumor (Procedure)
Treatment (pembrolizumab, gemcitabine hydrochloride)
INDUCTION: Patients receive pembrolizumab IV over 25-40 minutes on day 1 of cycles 1-4. Patients also receive gemcitabine hydrochloride intravesically on days 1, 8 and 15 of cycles 1 and 2. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Beginning cycle 5, patients with no evidence of disease after induction receive pembrolizumab IV over 25-40 minutes and gemcitabine intravesically on day 1 of each cycle. Treatment repeats every 3 weeks for 12 cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients with T1 tumors undergo a re-staging TURBT within 60 days of registration. Patients also undergo urine and blood sample collection, bladder biopsy, cystoscopy, CT and MRI throughout the study.
干预措施: Biopsy Procedure (Procedure)
Treatment (pembrolizumab, gemcitabine hydrochloride)
INDUCTION: Patients receive pembrolizumab IV over 25-40 minutes on day 1 of cycles 1-4. Patients also receive gemcitabine hydrochloride intravesically on days 1, 8 and 15 of cycles 1 and 2. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Beginning cycle 5, patients with no evidence of disease after induction receive pembrolizumab IV over 25-40 minutes and gemcitabine intravesically on day 1 of each cycle. Treatment repeats every 3 weeks for 12 cycles in the absence of disease progression or unacceptable toxicity.
Additionally, patients with T1 tumors undergo a re-staging TURBT within 60 days of registration. Patients also undergo urine and blood sample collection, bladder biopsy, cystoscopy, CT and MRI throughout the study.
干预措施: Gemcitabine Hydrochloride (Drug)
结局指标
主要结局
Complete response rate in the carcinoma in situ (CIS) subpopulation
时间窗: At 6 months (end of cycle 8, week 25)
A complete response, only for patients with a CIS component, is a cystoscopy without evidence of bladder tumor and negative biopsy (including directed biopsies to any suspicious areas and in addition random bladder biopsies including trigone, left lateral wall, right lateral wall, posterior bladder, dome of bladder, and the prostatic urethra in men), and negative cytology for high grade disease.
Event-free survival at 18 months
时间窗: From the date of study registration to the first documentation of an event or death whichever comes first, assessed up to 18 months
For patients without a documented event and who are still alive, they will be censored at last disease assessment. For patients who start any subsequent ant-cancer therapy without any reported events will be censored at their last disease assessment. will be obtained with a Kaplan-Meier estimator (using the Greenwood formula to estimate the variance) for the entire 153 patient group consisting of patients with CIS, CIS with Ta/T1 or Ta or T1 disease. A 90% confidence interval will be generated for the 18-month EFS estimate.
次要结局
- Incidence of adverse events(Up to 5 years post treatment)
- Duration of response (DOR)(From the time a patient had a documented response (the time would start at the time a response was first noted) until disease-progression, assessed up to 5 years)
- Progression-free survival (PFS)(From the date of study registration to the date of progression or death due to any cause, whichever occurs first, assessed up to 5 years)
- Overall survival (OS)(From the date of study registration to date of death due to any cause, assessed up to 5 years)
- Cystectomy-free survival(From the date of study registration to the date of cystectomy for all patients)
- Recurrence free survival (RFS)(From the date of study registration to the first documentation of recurrence or death due to any cause, assessed up to 5 years)