A Multi-centre Randomised Study of Induction Chemotherapy Followed by Capecitabine (+/-Nelfinavir) With High or Standard Dose Radiotherapy for Locally Advanced Non-metastatic Pancreatic Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 159
- 试验地点
- 23
- 主要终点
- Overall survival in LANPC
研究概览
简要总结
This study will evaluate the role of increasing radiotherapy dose and addition of nelfinavir to chemoradiotherapy (CRT) in patients with inoperable pancreatic cancer that has not spread beyond the pancreas.
Currently in the United Kingdom (UK), either chemotherapy alone or chemotherapy followed by CRT can be used in the management of inoperable pancreatic cancer that has not spread. CRT consists of 25-30 radiotherapy treatments in combination with chemotherapy. Although this treatment is effective in controlling local symptoms and slowing down the pace of cancer, in most cases it is unable to shrink it enough to make it operable. Some of the reasons for this could be the lack of oxygen and lack of blood flow within the tumour making it resistant to the effects of CRT. This study will investigate whether increasing the dose of radiotherapy, or increasing the oxygen and blood supply to the tumour by giving nelfinavir, or a combination of both, can improve outcomes. We also want to know what the additional toxicities from such intensive approaches are.
All participants will initially receive 12 weeks of chemotherapy, and those with stable or responding disease will receive further study treatment. The treatment allocation, initially to one of the four options, but as of 26Feb2020, to one of two options, as outlined below will be done at random by computer and neither the doctor nor the patient can choose the treatment option. The process of randomisation ensures that all treatment arms are equally balanced in terms of patient and tumour characteristics, and to reduce the possibility of bias.
The study will consist of 2 stages. In the 1st stage we aimed to find the right dose of nelfinavir to combine with CRT, requiring 27 participants of whom up to 18 will receive nelfinavir together with CRT. The Maximum Tolerated Dose of nelfinavir for Stage 2 has been established as 1250mg bd based on the data of 4 patients in the Stage 1, 1250mg cohort. In the 2nd stage, we want to find out the benefits of this approach over and above standard treatments and therefore we will recruit the order of 168 participants and allocate 96 to 1 of the 4 following treatment arms (As from 26Feb2020, randomisation will continue into one of two arms):
Arm A: Nelfinavir together with CRT (arm A closed on 26Feb2020) Arm B: CRT (without nelfinavir) Arm C: Nelfinavir together with CRT (but using a higher than conventional dose of radiotherapy) (arm C closed on 26Feb2020) Arm D: CRT without nelfinavir (but using a higher than conventional dose of radiotherapy) Participants allocated to any of the two arms, following closure of Arms A & C on 26Feb2020, will receive one further cycle of chemotherapy prior to starting chemoradiotherapy (without nelfinavir). This is to allow time for radiotherapy planning.
Participants who are ineligible or refuse randomisation will be treated as per local standard but will remain in the study for follow up every 12 weeks. Their data will contribute to an Overall Survival (OS) analysis.
详细描述
Pancreatic cancer has a poor outcome. Approximately 8000 cases are diagnosed in the UK each year and approximately 8000 patients die from the disease [1]. 20% of the patients are operable at diagnosis, 30-40% have locally advanced inoperable disease [LANPC] and another 40-50% have metastatic disease. Patients with LANPC have a relatively better prognosis compared to patients with metastatic disease (median overall survival 10-12 months and 5-6 months respectively). Currently, treatment options for LANPC include:
- Primary chemotherapy
- Primary chemoradiation (CRT) followed by adjuvant chemotherapy
- Induction chemotherapy followed by CRT
Studies investigating primary chemotherapy vs. primary CRT have reported overall survival between ten to 12 months and there are conflicting reports as to whether chemotherapy alone or primary CRT is superior [2, 3].
More recently, there has been a shift to using induction chemotherapy to pre-select patients who are suitable for CRT. The LAP07 trial [4] compared chemotherapy alone (gemcitabine with/without erlotinib) versus same chemotherapy for 4 months followed by consolidation capecitabine-based CRT. The study aimed to recruit over 700 patients but closed early on recommendation of IDMC following a planned interim analysis after 442 patients. This study failed to show superiority of consolidation CRT over continuing chemotherapy alone (median overall survival 15.2 months vs. 16.4 months, log rank p=0.8) but confirmed good tolerance of CRT in multi-institutional setting (Grade 3/4 gastro-intestinal toxicity 5.9%; Grade 3/4 neutropenia 3.1%) [4]. The investigators concluded that both chemotherapy alone and consolidation CRT are options for this group of patients and further trials should investigate intensifying both radiotherapy (RT) and chemotherapy strategies.
In the UK, the recently reported SCALOP trial randomised patients to gemcitabine or capecitabine based CRT following 4 months of induction GEMCAP chemotherapy [5]. 114 patients were recruited from 28 centres over 2 years, and 74 non-progressive patients were randomised to CRT. This study demonstrated UK's feasibility to recruit to CRT trials in pancreatic cancer and deliver high quality RT within a well-controlled Radiotherapy Trials Quality Assurance programme coordinated by the NCRI RTTQA Group. SCALOP suggested superiority of capecitabine-based CRT over gemcitabine based-CRT in terms of overall survival (median overall survival 15.2 vs. 13.4 months, HR 0.39, p=0.012) and treatment related Grade 3/4 toxicity (haematological 0% vs. 18%, p=0.008; non-haematological 12% vs. 26%, p=0·12). The outcome/toxicity in the cape-RT arm was very similar to that reported in LAP07 study, and capecitabine could now be considered as the preferred radio-sensitizer in the context of pancreatic CRT.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Arm A
12 weeks (3 cycles) of induction Gemcitabine and Nab-paclitaxel (GEMABX) chemotherapy then 1 cycle of GEMABX* whilst radiotherapy (RT) planned then capecitabine (830mg/m2 oral bd) + Nelfinavir** + 50.4 Grays (Gy) in 28# (arm A closed on 26Feb2020 due to lack of efficacy of nelfinavir)
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.
干预措施: nab-paclitaxel (Drug)
Arm A
12 weeks (3 cycles) of induction Gemcitabine and Nab-paclitaxel (GEMABX) chemotherapy then 1 cycle of GEMABX* whilst radiotherapy (RT) planned then capecitabine (830mg/m2 oral bd) + Nelfinavir** + 50.4 Grays (Gy) in 28# (arm A closed on 26Feb2020 due to lack of efficacy of nelfinavir)
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.
干预措施: 50.4Gy in 28# (Radiation)
Arm A
12 weeks (3 cycles) of induction Gemcitabine and Nab-paclitaxel (GEMABX) chemotherapy then 1 cycle of GEMABX* whilst radiotherapy (RT) planned then capecitabine (830mg/m2 oral bd) + Nelfinavir** + 50.4 Grays (Gy) in 28# (arm A closed on 26Feb2020 due to lack of efficacy of nelfinavir)
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.
干预措施: Nelfinavir (Drug)
Arm A
12 weeks (3 cycles) of induction Gemcitabine and Nab-paclitaxel (GEMABX) chemotherapy then 1 cycle of GEMABX* whilst radiotherapy (RT) planned then capecitabine (830mg/m2 oral bd) + Nelfinavir** + 50.4 Grays (Gy) in 28# (arm A closed on 26Feb2020 due to lack of efficacy of nelfinavir)
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.
干预措施: Capecitabine (Drug)
Arm A
12 weeks (3 cycles) of induction Gemcitabine and Nab-paclitaxel (GEMABX) chemotherapy then 1 cycle of GEMABX* whilst radiotherapy (RT) planned then capecitabine (830mg/m2 oral bd) + Nelfinavir** + 50.4 Grays (Gy) in 28# (arm A closed on 26Feb2020 due to lack of efficacy of nelfinavir)
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.
干预措施: Gemcitabine (Drug)
Arm B
12 weeks (3 cycles) of induction GEMABX chemotherapy then 1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + 50.4Gy in 28#
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.
干预措施: nab-paclitaxel (Drug)
Arm B
12 weeks (3 cycles) of induction GEMABX chemotherapy then 1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + 50.4Gy in 28#
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.
干预措施: 50.4Gy in 28# (Radiation)
Arm B
12 weeks (3 cycles) of induction GEMABX chemotherapy then 1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + 50.4Gy in 28#
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.
干预措施: Capecitabine (Drug)
Arm B
12 weeks (3 cycles) of induction GEMABX chemotherapy then 1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + 50.4Gy in 28#
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.
干预措施: Gemcitabine (Drug)
Arm C
12 weeks (3 cycles) of induction GEMABX chemotherapy then
1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + Nelfinavir** + 60Gy in 30# (arm C closed on 26Feb2020 due to lack of efficacy of nelfinavir)
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15
干预措施: nab-paclitaxel (Drug)
Arm C
12 weeks (3 cycles) of induction GEMABX chemotherapy then
1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + Nelfinavir** + 60Gy in 30# (arm C closed on 26Feb2020 due to lack of efficacy of nelfinavir)
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15
干预措施: 60Gy in 30# (Radiation)
Arm C
12 weeks (3 cycles) of induction GEMABX chemotherapy then
1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + Nelfinavir** + 60Gy in 30# (arm C closed on 26Feb2020 due to lack of efficacy of nelfinavir)
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15
干预措施: Nelfinavir (Drug)
Arm C
12 weeks (3 cycles) of induction GEMABX chemotherapy then
1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + Nelfinavir** + 60Gy in 30# (arm C closed on 26Feb2020 due to lack of efficacy of nelfinavir)
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15
干预措施: Gemcitabine (Drug)
Arm D
12 weeks (3 cycles) of induction GEMABX chemotherapy then
1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + 60Gy in 30#
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.
干预措施: nab-paclitaxel (Drug)
Arm D
12 weeks (3 cycles) of induction GEMABX chemotherapy then
1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + 60Gy in 30#
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.
干预措施: 60Gy in 30# (Radiation)
Arm D
12 weeks (3 cycles) of induction GEMABX chemotherapy then
1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + 60Gy in 30#
*1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.
干预措施: Gemcitabine (Drug)
结局指标
主要结局
Overall survival in LANPC
时间窗: From date of registration until date of first documented (death by any cause), assessed up until Last Patient Last Visit (43 months)
RT dose question (50.4Gy v 60Gy): Overall survival (OS) (time from registration to event (death by any cause); patients who are not observed to die during the course of the trial will be censored at the last known date alive prior to end of trial date)
Progression free survival
时间窗: From date of registration until date of first documented progression or death ( if death occurred without progression), assessed up until last patient last visit (43 months).
Concurrent biological question (± Nelfinavir): Progression Free Survival (PFS) (time from registration to event (progression or death if death occurred without progression). Patients who are not assessed to have disease progression and are not observed to die during the course of the trial will be censored at the last known progression free follow-up date).
次要结局
- Concurrent biological question: resection rates(12 months from date of registration)
- RT dose question: resection rates,(12 months from date of registration)
- Concurrent biological question: treatment compliance measured using patient diary cards(12 months from date of registration)
- RT dose question: PFS(12 months from date of registration)
- Concurrent biological question: Toxicity (Serious Adverse Events scored by using NCI CTCAE v4.03),(12 months from date of registration)
- Concurrent biological question: overall survival(12 months from date of registration)
- Quality of life assessment by PAN26 questionnaire(Quality of life using PAN26 questionnaire was assessed at baseline, month 4 , 8 30, 39, 52 .)
- Quality of life assessment by the EQ-5D questionnaire(Quality of life using the EQ-5D questionnaire was assessed at baseline, month 4 , 8 30, 39, 52 .)
- CA19-9 level, 1-year local control rate(12 months from date of registration)
- RT dose question: 12-month OS rate,(12 months from date of registration)
- Disease response(12 months from date of registration)
- Quality of life assessment by EORTC QLQ-C30 questionnaire(Quality of life using EORTC QLQ-C30 questionnaire was assessed at baseline, month 4 , 8 30, 39, 52 .)