Phase I Dose Escalation of pAlliative Radiotherapy With Anti-PD1 Antibody Pembrolizumab in Thoracic Tumours
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose (MTD) of pembrolizumab that can be safely combined with radiotherapy (RT) in the absence of dose limiting toxicity (DLT) assessed by CTCAEv4
研究概览
简要总结
Lung cancer is the second most common cancer in the UK with around 43,500 new patients diagnosed each year. About 69% of patients are diagnosed with advanced stage disease and at present these patients would be expected to survive for less than 12 months. These statistics therefore show the need for the development of new effective drugs in the treatment of advanced Lung cancer.
Recent trial results have shown the efficacy of immunotherapy in treating several types of tumours including lung cancer. These tumours are known to express a high level of a glycoprotein called PDL1 which is a component of the PD1 pathway. In cancer the PD1 pathway can be hijacked by tumours leading to the immune system being suppressed. The aim of the new drug Pembrolizumab is to restart the PD1 pathway and use the immune system to help fight the cancer cells. Radiotherapy has also been shown to cause cancer to increase production of the proteins that can block the immune system. Therefore it has been proposed that combine of new immunotherapy agent such as pembrolizumab and radiotherapy in the treatment of lung cancer will allow more cancer cells to be killed through the immune system.
The purpose of this study is to see if pembrolizumab can safety be combined with standard palliative radiotherapy in patients with lung cancer. In addition once the patients have completed their course of radiotherapy they will remain on pembrolizumab alone and the study will look at how well this treatment regimen can control the growth of the cancer.
详细描述
- Risk and burden for patients
Patients in the first part of this study have cancer that is no longer responding to standard anticancer drug treatments.The phase 1 nature of this study means that the trial intervention may not have any additional benefit for patients who take part in the study.
The study itself carries a number of potential burdens:
- Study drug and radiotherapy:
Although the study drug safety effects have previously been assessed in NSCLC the side effects caused by the addition of radiotherapy is unconfirmed. These risks will be managed as much as possible by cautious dose escalation: as with all phase 1 studies, the data from each cohort will be reviewed by a safety review committee before deciding whether to increase the dose for subsequent cohorts.
Participants will be reviewed regularly by experienced clinicians while having the study treatment. Comprehensive assessments for safety will be carried out.
- Burden of frequent hospital visits and tests:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 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
- •Be willing and able to provide written informed consent for the trial.
- •Have measurable disease based on RECIST 1.
- •Histologically verified NSCLC including squamous cell carcinoma, adenocarcinoma, adenosquamous or large cell anaplastic carcinoma; requiring palliative radiotherapy for which no curative therapy exists will be recruited into the trial.
- •Patients are permitted to have extrathoracic disease which will not be encompassed in the radiotherapy field. This disease will be assessed for abscopal response
- •Ability to tolerate a course of palliative radiotherapy to the lung.
- •Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumour lesion.
- •Have a performance status of 0-2 on the ECOG Performance Scale.
- •Demonstrate adequate organ function, all screening labs should be performed within 10 days of confirmation of eligibility.
- •Patient's lung function tests at baseline should have an FEV1 > 0.8L or > 30%.
- •See protocol section.
排除标准
- •Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
- •Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
- •Previous radiotherapy to the lung
- •Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
- •Note: Patients with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
- •Note: If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- •Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
- •Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require the use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
- •Has evidence of interstitial lung disease or active, noninfectious pneumonitis.
- •Has received prior therapy with an antiPD1, antiPDL1, antiPDL2, antiCD137, or anti Cytotoxic T-lymphocyte associated antigen4 (CTLA4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways).
- •See protocol section.
研究组 & 干预措施
High Dose Radiotherapy Arm
Pembrolizumab and radiotherapy
干预措施: Radiotherapy (Radiation)
High Dose Radiotherapy Arm
Pembrolizumab and radiotherapy
干预措施: Pembrolizumab (Drug)
Low Dose Radiotherapy Arm
Pembrolizumab and radiotherapy
干预措施: Pembrolizumab (Drug)
Low Dose Radiotherapy Arm
Pembrolizumab and radiotherapy
干预措施: Radiotherapy (Radiation)
结局指标
主要结局
Maximum tolerated dose (MTD) of pembrolizumab that can be safely combined with radiotherapy (RT) in the absence of dose limiting toxicity (DLT) assessed by CTCAEv4
时间窗: up to 24 months
Toxicity rate of DLTs assessed by CTCAEv4
时间窗: two months after the last fraction of RT has been administered
次要结局
- Progression free survival rates will be calculated at 6 and 12 months, respectively(6 and 12 months)
- Overall survival rates will be calculated at 6 and 12 months, respectively(6 and 12 months)
- Progression free survival rates will be calculated at 6 and 12 months for PDL-1 strong patients, respectively(6 and 12 months)
- Overall survival rates will be calculated at 6 and 12 months for PDL-1 strong patients, respectively(6 and 12 months)
- Duration of clinical benefit, as assessed by RECIST v1.1(6 months and 1 year)
- Compare response rates, as assessed by RECIST v1.1, between squamous and non-squamous histological sub-types(6 months and 1 year)