Phase II Trial in Inoperable œsophageal Cancer Evaluating the Feasibility of the Combination of Definitive Chemoradiation With the Immune Checkpoint Blockers Nivolumab +/- Ipilimumab
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 8
- 试验地点
- 7
- 主要终点
- 12-Month Progression-free survival using RECIST 1.1
研究概览
简要总结
The main objective of the trial is to assess the feasibility and the safety of the addition of immunotherapy with PD-1 antibody nivolumab +/- CTLA-4 antibody ipilimumab to concomitant chemoradiation therapy (CRT) in inoperable patients with early or locally advanced oesophageal cancer and to select the more promising experimental arm among the two possible combinations in terms of activity (based on progression free survival (PFS) at 12 months according to RECIST 1.1) for further evaluation in a phase III trial.
The secondary objectives will aim to evaluate progression-free survival, failure-free survival and overall survival and pattern of progression (including incidence of distance metastasis).
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
- •Histologically proven oesophageal squamous cell carcinoma or adenocarcinoma
- •Both early stage and locally advanced tumor patients (according to TNM staging version 8):
- •T1, N1-3, M0 after complete work-up
- •T2, N0-3, M0 after complete work-up
- •T3, N0-3, M0
- •Patient eligible for definitive chemoradiation and not considered for primary surgery after multidisciplinary meeting decision or patient refuses to undergo surgery
- •Subject must be previously untreated with systemic treatment given as primary therapy for advanced or metastatic disease
- •At least one measurable lesion by CT scan or MRI based on RECIST version 1.1 with radiographic tumor assessment performed within 28 days prior to randomization
- •Availability of adequate tissue in terms of quality and quantity for immunohistochemical staining for PDL-1
- •WHO performance status 0 or 1
- •Adequate organ function within 14 days prior to randomization
排除标准
- •Cancer of cervical oesophagus (15 to 19 cm from dental ridge)
- •Known Her2 positive adenocarcinoma
- •Weight loss > 15 % over the last 3 months without improvement after nutritional support
- •Patient with cardiac dysfunction e.g. symptomatic congestive heart failure, uncontrolled hypertension
- •Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS), hepatitis B or hepatitis C.
- •Any prior treatment for advanced disease including treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
- •Live vaccines within 30 days prior to the first dose of study therapy. Examples of live vaccines include, but are not limited to the following: measles, mumps, rubella, chicken pox, yellow fever, H1N1 flu, rabies, BCG, and typhoid vaccine
- •History of hypersensitivity to study drugs or any excipient (refer to SmPCs for ipilimumab, nivolumab, 5-FU and oxaliplatin)
- •Current participation or treatment with an investigational agent or use of an investigational agent within 4 weeks of the first dose of study treatment
- •Serious comorbidity or life expectancy less than one year
- •Contraindication to chemoradiation therapy
- •Treatment history of radiotherapy
- •Child-Pugh B/C and patients with history of acute or chronic pancreatitis
- •Patient with Type I diabetes mellitus, or skin disorders
- •Known severe systemic autoimmune disease affecting the lungs or the bowel
- •Known contraindication to CT scans with IV contrast
- •Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 15 days prior to enrollment
- •Active autoimmune disease that has required systemic treatment in past 2 years
- •Autoimmune paraneoplastic syndrome requiring immunosuppressive or dedicated treatment
- •History of any other hematologic or primary solid tumor malignancy, unless in remission for at least 5 years.
研究组 & 干预措施
Arm A: Chemoradiation + Nivolumab
All patients will receive standard fractionation radiation therapy (RT) scheme: 50Gy in 25 fractions over 5 weeks (i.e. 2Gy per fraction), concurrently with 3 cycles of 2 weeks of FOLFOX followed by 3 cycles of 2 weeks of FOLFOX without RT.
Induction phase: Nivolumab IV 240 mg on days 1, 15 and 29 followed by a maintenance phase (to start on day 43) of Nivolumab IV 240 mg q2 weekly for up to 1 year.
干预措施: Nivolumab (Drug)
Arm A: Chemoradiation + Nivolumab
All patients will receive standard fractionation radiation therapy (RT) scheme: 50Gy in 25 fractions over 5 weeks (i.e. 2Gy per fraction), concurrently with 3 cycles of 2 weeks of FOLFOX followed by 3 cycles of 2 weeks of FOLFOX without RT.
Induction phase: Nivolumab IV 240 mg on days 1, 15 and 29 followed by a maintenance phase (to start on day 43) of Nivolumab IV 240 mg q2 weekly for up to 1 year.
干预措施: Chemoradiation (Other)
Arm B: Chemoradiation + Nivolumab + Ipilimumab
Same as arm A + induction phase: Ipilimumab IV 1 mg/kg on day 1 followed by a maintenance phase (to start on day 43) of Ipilimumab IV 1 mg/kg q6 weekly for up to 1 year
干预措施: Nivolumab (Drug)
Arm B: Chemoradiation + Nivolumab + Ipilimumab
Same as arm A + induction phase: Ipilimumab IV 1 mg/kg on day 1 followed by a maintenance phase (to start on day 43) of Ipilimumab IV 1 mg/kg q6 weekly for up to 1 year
干预措施: Ipilimumab (Drug)
Arm B: Chemoradiation + Nivolumab + Ipilimumab
Same as arm A + induction phase: Ipilimumab IV 1 mg/kg on day 1 followed by a maintenance phase (to start on day 43) of Ipilimumab IV 1 mg/kg q6 weekly for up to 1 year
干预措施: Chemoradiation (Other)
结局指标
主要结局
12-Month Progression-free survival using RECIST 1.1
时间窗: 3.8 years from first patient in
The analysis of the 12-Month Progression-free survival rate (PFS-12) will be done when all patients achieved at least 15 months follow-up (12 months for the primary endpoint plus 100 days after the end of the protocol treatment).
次要结局
- Best overall response according to RECIST 1.1(3.8 years from first patient in)
- Pattern of first cause of progression (either local relapse/progression,either regional relapse/progression, either distant metastasis)(3.8 years from first patient in)
- Progression-free survival using RECIST 1.1(3.8 years from first patient in)
- Failure-free survival(3.8 years from first patient in)
- Overall survival(3.8 years from first patient in)
- Percentage of patients receiving the planned chemoradiation(3.8 years from first patient in)
- Relative dose intensity of oxaliplatinum(3.8 years from first patient in)
- Relative dose intensity of 5FU(3.8 years from first patient in)