A Phase Ib/II, Open-Label Study of the Safety and Pharmacology of Atezolizumab Administered With or Without Bacille Calmette-Guérin in Patients With High-Risk Non-Muscle-Invasive Bladder Cancer
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 24
- 试验地点
- 8
- 主要终点
- Percentage of Participants With Adverse Events
研究概览
简要总结
This Phase Ib/II study is designed to assess the safety, tolerability, pharmacokinetics, immunogenicity, patient reported outcomes (PROs), and preliminary anti-tumor activity of atezolizumab administered by intravenous (IV) infusion alone and in combination with intravesical BCG in high-risk NMIBC participants. The study will be conducted in following cohorts: Cohort 1A, Cohort 1B, Cohort 2, and Cohort 3. Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg) every 3 weeks (q3w) for a maximum of 96 weeks. BCG will be administered to evaluate dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), or maximum administered dose (MAD). De-escalation will be allowed for up to three dose levels of BCG (full dose [50 mg], 66 percent [%] of a full dose, and 33% of a full dose [Cohort 1B only]). After the MTD or MAD is determined for Cohort 1B, this dose will be used for all subsequent participants enrolled into Cohorts 1B, 2, and 3, unless the MTD is determined to be 33% of a full BCG dose. If MTD is determined to be 33% of a full BCG dose, then, no participants will be enrolled into Cohorts 2 and 3 until an assessment of the safety and activity of the combination of atezolizumab plus 33% of a full BCG dose is completed.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Histologically confirmed non-muscle-invasive transitional cell carcinoma (TCC) of the bladder with carcinoma in-situ (CIS)
- •High-risk NMIBC defined by the following:
- •BCG-unresponsive NMIBC:
- •Persistence of high-grade CIS at 6 months following an adequate course of BCG; or Stage/grade progression at 3 months after induction BCG; or Recurrence of high-grade CIS after achieving a disease-free state (i.e., CR) following induction of an adequate course of BCG that occurs less than (<) 6 months after the last exposure to BCG
- •BCG-relapsing NMIBC:
- •Recurrence of high-grade CIS after achieving a disease-free state following induction of an adequate course of BCG that occurs greater than or equal to (>/=) 6 months after the last exposure to BCG
- •Very high-risk (VHR) BCG-naïve NMIBC:
- •VHR NMIBC, defined as having at least 1 of the following: Multiple and/or large (greater than [>] 3 centimeters [cm]) T1, (HG/G3) tumors; T1, (HG/G3) tumor with concurrent CIS; T1, G3 with CIS in prostatic urethra; Micropapillary variant of non-muscle invasive urothelial carcinoma
- •For BCG-unresponsive and BCG-relapsing NMIBC, participants must have received an adequate course of BCG
- •Resection of all pTa/pT1 papillary disease
- •No prior radiation to bladder or pelvic region
- •Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to (</=) 2;
- •Life expectancy >/=12 weeks
- •Adequate hematologic and end-organ function
- •Creatinine clearance >/=30 milliliters per minute (mL/min) (calculated using the Cockcroft-Gault formula)
- •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 5 months after the last dose of study drug. Women must refrain from donating eggs during this same period.
- •For men receiving BCG: Agreement to remain abstinent (refrain from sexual intercourse) or use a condom
- •Tumor tissue biopsy within 60 days prior to study entry or availability of an archival specimen obtained within 60 days of study screening
排除标准
- •Evidence of locally advanced, metastatic, muscle-invasive, and/or extravesical bladder cancer
- •Any malignancy within 5 years prior to Cycle 1, Day 1
- •History of autoimmune disease, idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or active pneumonitis
- •Signs or symptoms of infection within 2 weeks prior to the first dose of study treatment
- •Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to the first dose of study treatment
- •Treatment with any approved anti-cancer therapy within 3 weeks prior to the first dose of study treatment
- •Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to the first dose of study treatment
- •Pregnant or lactating women, or women intending to become pregnant during the study
- •Prior allogeneic stem cell or solid organ transplantation
- •Positive test for human immunodeficiency virus (HIV)
- •Active hepatitis B or C and/or tuberculosis
- •Severe infections within 28 days prior to the first dose of study treatment
- •Significant cardiovascular disease
- •Major surgical procedure other than for diagnosis within 4 weeks prior to the first dose of study treatment, or anticipation of need for a major surgical procedure during the course of the study
- •Administration of a live/attenuated vaccine within 4 weeks prior to the first dose of study treatment, within 5 months following the administration of the last dose of study drug, or anticipation that such a live/attenuated vaccine will be required during the study
- •History of prior significant toxicity or intolerance to BCG requiring discontinuation of treatment
- •History of prior systemic BCG infection
- •History of immunosuppression, or conditions associated with congenital or acquired immune deficiency
- •Concurrent febrile illness, urinary tract infection, or gross hematuria
- •Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies
- •Treatment with systemic immunostimulatory agents within 6 weeks or five half-lives of the drug, whichever is shorter, prior to the first dose of study treatment
- •Treatment with systemic immunosuppressive medications within 2 weeks prior to the first dose of study treatment, or anticipated requirement for systemic immunosuppressive medications during the trial
研究组 & 干预措施
Cohort 1A: Atezolizumab (BCG-unresponsive NMIBC)
Participants will receive atezolizumab 1200 mg IV infusion q3w, for a maximum of 32 doses or 96 weeks of therapy, whichever comes first.
干预措施: Atezolizumab (Drug)
Cohort 1B: Atezolizumab + BCG (BCG-unresponsive NMIBC)
During BCG induction course (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses. During BCG maintenance course 1 (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of three doses. Optional BCG maintenance courses 2-5 (each 24 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of eight doses per course plus BCG at the assigned dose weekly for a total of three doses per course.
干预措施: Atezolizumab (Drug)
Cohort 1B: Atezolizumab + BCG (BCG-unresponsive NMIBC)
During BCG induction course (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses. During BCG maintenance course 1 (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of three doses. Optional BCG maintenance courses 2-5 (each 24 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of eight doses per course plus BCG at the assigned dose weekly for a total of three doses per course.
干预措施: Bacille Calmette-Guérin (Biological)
Cohort 2: Atezolizumab + BCG (BCG-relapsing NMIBC)
During BCG induction course (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses. During BCG maintenance course 1 (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of three doses. During BCG maintenance courses 2-5 (each 24 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of eight doses per course plus BCG at the assigned dose weekly for a total of three doses per course.
干预措施: Atezolizumab (Drug)
Cohort 2: Atezolizumab + BCG (BCG-relapsing NMIBC)
During BCG induction course (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses. During BCG maintenance course 1 (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of three doses. During BCG maintenance courses 2-5 (each 24 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of eight doses per course plus BCG at the assigned dose weekly for a total of three doses per course.
干预措施: Bacille Calmette-Guérin (Biological)
Cohort 3: Atezolizumab + BCG (BCG-naive NMIBC)
During BCG induction course (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses. During BCG maintenance course 1 (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of three doses. During BCG maintenance courses 2-5 (each 24 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of eight doses per course plus BCG at the assigned dose weekly for a total of three doses per course.
干预措施: Atezolizumab (Drug)
Cohort 3: Atezolizumab + BCG (BCG-naive NMIBC)
During BCG induction course (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses. During BCG maintenance course 1 (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of three doses. During BCG maintenance courses 2-5 (each 24 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of eight doses per course plus BCG at the assigned dose weekly for a total of three doses per course.
干预措施: Bacille Calmette-Guérin (Biological)
结局指标
主要结局
Percentage of Participants With Adverse Events
时间窗: From Baseline up to end of study (up to approximately 4.3 years)
Percentage of participants with at least one adverse event during the study.
Cohort 1B: Percentage of Participants With DLTs of BCG
时间窗: Days 1-21
Percentage of participants with dose-limiting toxicities (DLT) of BCG in Cohort 1B.
Cohort 1B: MAD of BCG
时间窗: Days 1-21
Maximum administered dose (MAD) of BCG.
Percentage of Participants With Complete Response (CR) as Assessed by the Investigator on the Basis of Cystoscopy and Urine Cytology at Month 6
时间窗: 6 months
CR at 6 months after the start of study treatment as assessed by the investigator on the basis of cystoscopic assessment and urine cytology.
次要结局
- Cystectomy-Free Survival (CFS), as Assessed on the Basis of Cystoscopy and Urine Cytology(Time from first study treatment to cystectomy or death from any cause (up to approximately 4.3 years))
- Overall Survival(Time from first study treatment to death from any cause (up to approximately 4.3 years))
- Maximum Observed Serum Concentration of Atezolizumab (Cmax)(Cycle 1 Day 1 post-dose (Cycle length=21 days))
- Minimum Observed Serum Concentration of Atezolizumab (Cmin)(Pre-dose (0 hr) on Day 1 of Cycles 2, 3, 4 and 8 (Cycle length=21 days))
- Percentage of Participants With Anti-Therapeutic Antibody (ADA) Response to Atezolizumab(Pre-dose (0 hr) on Day 1 of Cycles 1, 2, 3, 4, 8, 16, 24 (Cycle length=21 days), end of atezolizumab treatment (up to 96 weeks), 120 days after end of atezolizumab treatment (up to 113 weeks))
- Percentage of Participants With CR as Assessed by the Investigator on the Basis of Cystoscopy and Urine Cytology at Month 3(3 months)
- Duration of CR, as Assessed on the Basis of Cystoscopy and Urine Cytology(From first occurence of a documented CR until the time of recurrence of NMIBC or death from any cause (up to approximately 4.3 years))
- Percentage of Participants With Recurrence-Free Survival (RFS), as Assessed on the Basis of Cystoscopy and Urine Cytology(6, 12 and 18 months)
- Bladder-Intact Disease-Free Survival (DFS), as Assessed on the Basis of Cystoscopy and Urine Cytology(From first study treatment to earliest evidence of progression to muscle-invasive disease in the bladder, regional pelvic progression, distant metastasis, bladder cancer-related death, or cystectomy or death from any cause (up to approximately 4.3 years))
- Progression-Free Survival (PFS), as Assessed on the Basis of Cystoscopy and Urine Cytology(Time from first study treatment to the first occurrence of progression to muscle-invasive disease or death from any cause (up to approximately 4.3 years))