NCT03387761已完成1 期
Phase 1B Study to Assess Safety and Efficacy of Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy (NABUCCO)
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 54
- 试验地点
- 3
- 主要终点
- Number of patients that had surgical resection <12 weeks after study start (Cohort 1)
研究概览
简要总结
In cohort 1 of this study, we used an attenuated schedule of neoadjuvant ipilimumab and nivolumab. In the multicenter extension (cohort 2), 30 patients were randomized between two neoadjuvant treatment schemes, both based upon an attenuated schedule of neoadjuvant ipilimumab and nivolumab.Both cohorts are completed.
详细描述
This is an open-label phase Ib trial to evaluate three different schedules of preoperative ipilimumab and nivolumab. Urothelial cancer patients will be included that are diagnosed with either:
- cT3-4aN0M0 OR
- T1-4aN1-3M0
Cohort 1 (n=24):
- Day 1: Ipilimumab 3 mg/kg
- Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg
- Day 43: Nivolumab 3 mg/kg
- Day 56-84: Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection
Patients in cohort 2 (n=30) were randomized between cohort 2a and 2b
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Willing and able to provide informed consent
- •Age ≥ 18 years
- •High-risk resectable urothelial cancer (upper urinary tract allowed) defined as stage III UC:
- •cT3-4aN0M0 OR cT1-4aN1-3M0
- •Refusal of neoadjuvant/induction cisplatin-based chemotherapy or patients in whom neoadjuvant cisplatin based therapy is not appropriate.
- •World Health Organization (WHO) performance Status 0 or
- •Urothelial cancer is the dominant histology (>70%).
- •Formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks from diagnostic TUR available (or any other FFPE tumor specimens for upper tract tumors).
- •Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.0x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, GFR>30 ml/min, AST ≤ 2.5 x ULN, ALT ≤2.5 x ULN, Bilirubin ≤1.5 X ULN
- •Negative pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential.
- •For female patients of childbearing potential to use a highly effecting form(s) of contraception (i.e. one that results in a low failure rate [<1% per year] when used consistently and correctly) and to continue its use for 180 days after the last dose of immunotherapy Adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms, oral contraceptives, intra-uterine device.
排除标准
- •Subjects with active autoimmune disease in the past 2 years. Patients with diabetes mellitus, properly controlled hypothyroidism or hyperthyroidism, vitiligo, psoriasis or other mild skin disease can still be included.
- •Documented history of severe autoimmune disease (e.g. inflammatory bowel disease, myasthenia gravis).
- •Prior CTLA-4 or PD-1/PD-L1-targeting immunotherapy.
- •Known history of Human Immunodeficiency Virus, positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA), active tuberculosis, or other active infection requiring therapy at the time of inclusion.
- •Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of adverse events
- •Medical condition requiring the use of immunosuppressive medications, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) will be allowed.
- •Use of other investigational drugs before study drug administration
- •Malignancy, other than urothelial cancer, in the previous 2 years, with a high chance of recurrence (estimated >10%). Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score
- •≤ 6, and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible.
- •Pregnant and lactating female patients.
- •Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis.
- •Severe infections within 4 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.
- •Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrolment, unstable arrhythmias, or unstable angina.
- •Previous intravenous chemotherapy for bladder cancer. Prior chemoradiation is allowed.
- •Patients in whom use of a colon segment for urinary diversion is planned
研究组 & 干预措施
Cohort 1: Ipi + Nivo
Experimental
- Day 1: Ipilimumab 3 mg/kg i.v.
- Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v.
- Day 43: Nivolumab 3 mg/kg i.v.
干预措施: Ipilimumab (Drug)
Cohort 1: Ipi + Nivo
Experimental
- Day 1: Ipilimumab 3 mg/kg i.v.
- Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v.
- Day 43: Nivolumab 3 mg/kg i.v.
干预措施: Nivolumab (Drug)
Cohort 2a: high-Ipi + low-Nivo
Experimental
- Day 1: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v.
- Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v.
- Day 43: Nivolumab 3 mg/kg i.v.
- Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection, day 56-84
干预措施: Ipilimumab (Drug)
Cohort 2a: high-Ipi + low-Nivo
Experimental
- Day 1: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v.
- Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v.
- Day 43: Nivolumab 3 mg/kg i.v.
- Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection, day 56-84
干预措施: Nivolumab (Drug)
Cohort 2b: low-Ipi + high-Nivo
Experimental
- Day 1: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg i.v.
- Days 22: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg i.v.
- Day 43: Nivolumab 3 mg/kg i.v.
- Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection, day 56-84
干预措施: Ipilimumab (Drug)
Cohort 2b: low-Ipi + high-Nivo
Experimental
- Day 1: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg i.v.
- Days 22: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg i.v.
- Day 43: Nivolumab 3 mg/kg i.v.
- Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection, day 56-84
干预措施: Nivolumab (Drug)
结局指标
主要结局
Number of patients that had surgical resection <12 weeks after study start (Cohort 1)
时间窗: At 12 weeks
Percentage of patients that underwent surgery within 12 weeks after study start were assessed
次要结局
- Efficacy of immunotherapy, assessed by by the percentage of pathological complete response rate (pCR) after cystectomy (Cohort 1, followed by Cohort 2a versus 2b)(At 12 weeks)
- Monitor peri-surgical complications.(Until 90 days after surgery.)
- ctDNA in plasma during follow-up(During follow-up and with disease recurrence)
- As part of regular follow-up after radical surgery, follow-up CT scans were made after 1 and 2 years.(Until 2 years after surgery (not part of primary study assessment))
- Explore whether radiomics-based predictive models can be established for immunotherapy responders vs non-responders (Cohort 1)(At 12 weeks)
- Provide an estimate of ≥grade 3 immune-related toxicity in cohorts 2a versus 2b(At 12 weeks)
- Differences in immune infiltrates in responders vs nonresponders(At 12 weeks)
- T-cell (dys)functionality as measured by comparing the transcriptome of tumor-specific T cells in intra-patient pre- and post therapy tissue(At 12 weeks)
研究者
研究点 (3)
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