A Multicentre Single Arm Phase II Trial Assessing the Efficacy of Immunotherapy, Chemotherapy and Stereotactic Radiotherapy to Metastases Followed by Definitive Surgery or Radiotherapy to the Primary Tumour, in Patients With Synchronous Oligo-metastatic Non-small Cell Lung Cancer
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 96
- 试验地点
- 15
- 主要终点
- Progression-free survival at 12 months
研究概览
简要总结
A multicentre single arm phase II trial assessing the efficacy of immunotherapy, chemotherapy plus stereotactic radiotherapy to metastases followed by definitive surgery or radiotherapy to the locoregional primary tumour, in patients with histologically-confirmed synchronous oligo-metastatic non-small cell lung cancer (NSCLC).
详细描述
Non-small cell lung cancer (NSCLC) continues to be the leading cause of cancer-related mortality worldwide. Even with adjustment for age NSCLC is responsible for almost 20% of cancer-related deaths. Recent years have brought tremendous progress in the understanding of the disease, its underlying biology and the development of effective therapies. Traditionally, NSCLC has been treated with surgery, platinum-based chemotherapy or radiotherapy alone or in combination, depending on tumour stage, tolerability of expected side effects and prognosis. Various strategies are currently being pursued in order to increase the patient population that may benefit from immunotherapy and to further improve the outcome of patients with NSCLC.
The CHESS clinical trial is for patients with NSCLC that has progressed to a small number of other parts of the body (oligo-metastatic) and has not been previously treated, or after surgical resection of a single metastasis (central nervous system or adrenal). The trial aims to reduce the risk of systemic progression and thereby improve progression free survival. Participants will receive induction treatment consisting of immunotherapy combined with platinum-based doublet chemotherapy and stereotactic body radiotherapy (SBRT) that will be given to all oligo-metastatic locations. SBRT started early and concurrently with immunotherapy aims at enhancing a postulated immune effect and simultaneously effectively control the macro-metastases.
Preclinical data have shown a strong immune-enhancing effect of radiotherapy, especially when delivered to small volumes, in high-single fraction doses and over a short period of time. Consequently, stereotactic body radiotherapy (SBRT) is currently being intensively investigated as a partner for systemic immunotherapy. Earlier clinical studies generated proof-of-principle data for the synergistic effects of combined radiotherapy and immunotherapy. Chemotherapy and high-dose radiotherapy are well known triggers of immunogenic cell death and are therefore highly promising partners for combination with immunotherapy.
The sub-group of patients with "oligometastatic" disease was originally described by Hellman and Weichselbaum in 1995. In line with this concept, the current NCCN and ESMO guidelines describe that Stage IV NSCLC patients presenting with solitary metastases can be treated with curative intent using local surgery and/or radiotherapy. Local treatment for oligo-metastatic NSCLC has been adopted rapidly in the oncological community and one reason is the progress made in the fields of surgery and radiotherapy, both becoming less toxic (minimally invasive surgery) and simultaneously less toxic and more effective (precision radiotherapy), respectively. SBRT allows treatment of small peripheral primaries and metastases at virtually all anatomical locations with a favourable therapeutic ratio of local tumour control rates >90% and low rates of toxicity. Simultaneously, minimally invasive surgery for early and locally advanced NSCLC today achieves excellent local tumour control with low rates of toxicity.
Patients with a limited number of metastases - oligometastatic disease - are currently treated with combined radical local treatment for all active lesions (locoregional primary and metastases) and their prognosis is better as compared to patients who receive systemic treatment only for widespread metastatic disease. However, the majority of patients still develop systemic disease progression indicating the urgent clinical need for more effective systemic treatment to control subclinical disease.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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-small cell lung cancer
- •Synchronous oligo-metastatic stage IV disease: maximum of three distant metastases, one of which must be extra-cerebral for stereotactic body radiotherapy (SBRT); Initial mediastinal staging is recommended (except for lymph nodes <1 cm on CT and PET-negative) preferentially by endobronchial ultrasound (EBUS); Neurosurgical resection of one single central nervous system (CNS) metastasis or laparoscopic resection of one adrenal metastasis before study inclusion is allowed (one extra-cerebral metastasis must be available for SBRT)
- •Able to understand and give written informed consent and comply with study procedures
- •Age ≥18 years
- •ECOG Performance Status 0-1
- •Availability of tumour tissue for translational research
- •Adequate haematological, renal and liver function
排除标准
- •Prior chemotherapy, radiotherapy or therapeutic surgery for NSCLC (an exception is the resection of one single CNS or adrenal metastasis, as above)
- •Activating driver mutation: epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), proto-oncogene receptor tyrosine kinase (ROS1)
- •More than three distant metastases
- •Brain metastases not amendable for radiosurgery or neurosurgery
- •Extracranial metastatic locations such as malignant ascites, pleural or pericardial effusion, diffuse lymphangiomatosis of skin or lung, diffuse bone marrow metastasis, abdominal masses/abdominal organomegaly, identified by physical exam that is not measurable by reproducible imaging techniques.
- •Primary lung cancer not suitable for radical therapy (pneumonectomy excluded)
- •History of leptomeningeal carcinomatosis
- •Major surgery or significant traumatic injury from which the patient has not recovered at least 28 days before enrolment
- •Any uncontrolled intercurrent illness, including but not limited to: ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease or serious chronic gastrointestinal conditions associated with diarrhea, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol
- •Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc) at screening.
- •Known positivity for human immunodeficiency virus (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice)
- •Active autoimmune disease requiring systemic treatment
- •Severe or uncontrolled cardiac disease requiring treatment
- •History of active primary immunodeficiency
- •History of allogeneic organ transplant
- •Receipt of live attenuated vaccines within 30 days prior to enrolment
- •Known allergies or hypersensitivity to trial drugs or to any excipient.
- •Women who are pregnant or in the period of lactation.
- •Sexually active men and women of childbearing potential who are not willing to use a highly effective contraceptive method during the trial and up to 90 days after last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab and tremelimumab combination therapy
研究组 & 干预措施
Immunotherapy, chemotherapy, radiotherapy and surgery
Durvalumab 1500 mg administered intravenously every 3 weeks for the first 4-6 cycles (during chemotherapy);
Tremelimumab 75mg administered intravenously every 3 weeks for the first 4-6 cycles (only cohort 2)
4-6 cycles of chemotherapy, carboplatin AUC5 every 3 weeks plus paclitaxel 175 mg/m2, every 3 weeks;
Stereotactic body radiotherapy (SBRT) of all oligo-metastatic lesions, in a maximum of 10 treatment fractions over 2 weeks, starting after week one of chemotherapy cycle 1 and completed within four weeks after start of durvalumab treatment;
Restaging at 3 months; if no disease progression, proceed to definitive local treatment (surgical resection of primary tumour or radiotherapy at a minimum dose of 60-66Gy to the primary tumour). Durvalumab continues at 1500 mg intravenously every 4 weeks until progression of disease or for a maximum of 1 year from start of treatment.
干预措施: Carboplatin (Drug)
Immunotherapy, chemotherapy, radiotherapy and surgery
Durvalumab 1500 mg administered intravenously every 3 weeks for the first 4-6 cycles (during chemotherapy);
Tremelimumab 75mg administered intravenously every 3 weeks for the first 4-6 cycles (only cohort 2)
4-6 cycles of chemotherapy, carboplatin AUC5 every 3 weeks plus paclitaxel 175 mg/m2, every 3 weeks;
Stereotactic body radiotherapy (SBRT) of all oligo-metastatic lesions, in a maximum of 10 treatment fractions over 2 weeks, starting after week one of chemotherapy cycle 1 and completed within four weeks after start of durvalumab treatment;
Restaging at 3 months; if no disease progression, proceed to definitive local treatment (surgical resection of primary tumour or radiotherapy at a minimum dose of 60-66Gy to the primary tumour). Durvalumab continues at 1500 mg intravenously every 4 weeks until progression of disease or for a maximum of 1 year from start of treatment.
干预措施: Tremelimumab (Drug)
Immunotherapy, chemotherapy, radiotherapy and surgery
Durvalumab 1500 mg administered intravenously every 3 weeks for the first 4-6 cycles (during chemotherapy);
Tremelimumab 75mg administered intravenously every 3 weeks for the first 4-6 cycles (only cohort 2)
4-6 cycles of chemotherapy, carboplatin AUC5 every 3 weeks plus paclitaxel 175 mg/m2, every 3 weeks;
Stereotactic body radiotherapy (SBRT) of all oligo-metastatic lesions, in a maximum of 10 treatment fractions over 2 weeks, starting after week one of chemotherapy cycle 1 and completed within four weeks after start of durvalumab treatment;
Restaging at 3 months; if no disease progression, proceed to definitive local treatment (surgical resection of primary tumour or radiotherapy at a minimum dose of 60-66Gy to the primary tumour). Durvalumab continues at 1500 mg intravenously every 4 weeks until progression of disease or for a maximum of 1 year from start of treatment.
干预措施: Stereotactic body radiation therapy (SBRT) (Radiation)
Immunotherapy, chemotherapy, radiotherapy and surgery
Durvalumab 1500 mg administered intravenously every 3 weeks for the first 4-6 cycles (during chemotherapy);
Tremelimumab 75mg administered intravenously every 3 weeks for the first 4-6 cycles (only cohort 2)
4-6 cycles of chemotherapy, carboplatin AUC5 every 3 weeks plus paclitaxel 175 mg/m2, every 3 weeks;
Stereotactic body radiotherapy (SBRT) of all oligo-metastatic lesions, in a maximum of 10 treatment fractions over 2 weeks, starting after week one of chemotherapy cycle 1 and completed within four weeks after start of durvalumab treatment;
Restaging at 3 months; if no disease progression, proceed to definitive local treatment (surgical resection of primary tumour or radiotherapy at a minimum dose of 60-66Gy to the primary tumour). Durvalumab continues at 1500 mg intravenously every 4 weeks until progression of disease or for a maximum of 1 year from start of treatment.
干预措施: Surgical resection - definitive local treatment. (Procedure)
Immunotherapy, chemotherapy, radiotherapy and surgery
Durvalumab 1500 mg administered intravenously every 3 weeks for the first 4-6 cycles (during chemotherapy);
Tremelimumab 75mg administered intravenously every 3 weeks for the first 4-6 cycles (only cohort 2)
4-6 cycles of chemotherapy, carboplatin AUC5 every 3 weeks plus paclitaxel 175 mg/m2, every 3 weeks;
Stereotactic body radiotherapy (SBRT) of all oligo-metastatic lesions, in a maximum of 10 treatment fractions over 2 weeks, starting after week one of chemotherapy cycle 1 and completed within four weeks after start of durvalumab treatment;
Restaging at 3 months; if no disease progression, proceed to definitive local treatment (surgical resection of primary tumour or radiotherapy at a minimum dose of 60-66Gy to the primary tumour). Durvalumab continues at 1500 mg intravenously every 4 weeks until progression of disease or for a maximum of 1 year from start of treatment.
干预措施: Radical radiotherapy - definitive local treatment. (Radiation)
Immunotherapy, chemotherapy, radiotherapy and surgery
Durvalumab 1500 mg administered intravenously every 3 weeks for the first 4-6 cycles (during chemotherapy);
Tremelimumab 75mg administered intravenously every 3 weeks for the first 4-6 cycles (only cohort 2)
4-6 cycles of chemotherapy, carboplatin AUC5 every 3 weeks plus paclitaxel 175 mg/m2, every 3 weeks;
Stereotactic body radiotherapy (SBRT) of all oligo-metastatic lesions, in a maximum of 10 treatment fractions over 2 weeks, starting after week one of chemotherapy cycle 1 and completed within four weeks after start of durvalumab treatment;
Restaging at 3 months; if no disease progression, proceed to definitive local treatment (surgical resection of primary tumour or radiotherapy at a minimum dose of 60-66Gy to the primary tumour). Durvalumab continues at 1500 mg intravenously every 4 weeks until progression of disease or for a maximum of 1 year from start of treatment.
干预措施: Durvalumab (Drug)
Immunotherapy, chemotherapy, radiotherapy and surgery
Durvalumab 1500 mg administered intravenously every 3 weeks for the first 4-6 cycles (during chemotherapy);
Tremelimumab 75mg administered intravenously every 3 weeks for the first 4-6 cycles (only cohort 2)
4-6 cycles of chemotherapy, carboplatin AUC5 every 3 weeks plus paclitaxel 175 mg/m2, every 3 weeks;
Stereotactic body radiotherapy (SBRT) of all oligo-metastatic lesions, in a maximum of 10 treatment fractions over 2 weeks, starting after week one of chemotherapy cycle 1 and completed within four weeks after start of durvalumab treatment;
Restaging at 3 months; if no disease progression, proceed to definitive local treatment (surgical resection of primary tumour or radiotherapy at a minimum dose of 60-66Gy to the primary tumour). Durvalumab continues at 1500 mg intravenously every 4 weeks until progression of disease or for a maximum of 1 year from start of treatment.
干预措施: Paclitaxel (Drug)
结局指标
主要结局
Progression-free survival at 12 months
时间窗: Assessed from the date of enrolment to completion of treatment at 12 months.
The PFS rate at 1-year is the primary endpoint of this trial and it is defined as the rate of patients without a PFS event at 1-year after enrolment. The rate will be estimated as the percentage of patients without a PFS event over the total number of patients who have completed a 1-year follow-up period after the enrolment. PFS is defined as the time from the date of enrolment until documented progression or death, if progression is not documented. Progression is defined as the development of new metastatic lesions or local progression of resected or irradiated metastases or primary tumour, assessed according to RECIST criteria version 1.1
次要结局
- Symptom-specific and global quality of life: The Lung Cancer Symptom Scale(Assessed at trial entry, until 6 months after treatment start and at 12 months from enrolment.)
- Overall survival(Time from date of enrolment until death from any cause. Assessed for up to 30 months.)
- Distant progression-free survival(Assessed from the date of enrolment for up to 12 months.)
- Overall response(Assessed from the start of protocol treatment across all time points until the end of follow-up, assessed for up to 30 months.)
- Toxicity before and after surgery/radiotherapy(Adverse events will be collected from the date of consent until 90 days after the completion of treatment.)
- Pattern of disease progression(Assessed from the date of enrolment until progression, from enrolment up to 12 months.)
- Response to induction therapy(Assessed from the start of protocol treatment until the 3-month restaging)
- Duration of response(Assessed from the date of enrolment for up to 12 months.)