编译：Temperance
来源：肿瘤资讯
1430TiP：STIMULI: A randomised open-label phase II trial of consolidation with nivolumab and ipilimumab in limited-stage SCLC after standard of care chemo-radiotherapy conducted by ETOP and IFCT
STIMULI: ETOP及IFCT进行的开放性II期随机临床试验，观察已经完成标准化疗联合治疗后的局限期小细胞肺癌患者接受nivolumab联合ipilimumab治疗的效果
Background: Preliminary results from trial CheckMate 032, targeting two distinct inhibitory immune checkpoints combining nivolumab, an anti-PD1 IgG1 monoclonal antibody and ipilimumab, an anti-CTLA4 IgG1 monoclonal antibody, demonstrate very promising 31% objective response rate (ORR) and 48% one-year overall survival (OS) in pre-treated advanced SCLC. This treatment option will be explored in a consolidation setting after curative-intent chemotherapy, chest radiotherapy (RT) and prophylactic cranial irradiation (PCI) for LD-SCLC.
Trial design: STIMULI is an open-label, randomised, two-arm, phase II clinical trial. Inclusion is restricted to stage I-IIIB untreated LD-SCLC patients (pts) with adequate organ and pulmonary function, and no history of auto-immune disease. Hyper- or conventionally fractionated chest RT is administered concomitantly to 4 cycles of Cis-/carboplatin plus etoposide, followed by PCI. After completion of this standard treatment, non-progressing pts are randomised 1:1 to consolidation (induction and maintenance) or observation. Induction consists of four 3-week cycles of ipilimumab 3mg/kg plus nivolumab 1mg/kg, and is followed by maximally 12 months of nivolumab 240mg every 2 weeks. OS and progression-free survival (PFS) are co-primary endpoints. ORR, time to treatment failure and tolerability are secondary endpoints. A total of 325 pts are expected to be enrolled in the standard treatment phase, in order for 260 pts to be randomised, with a target hazard ratio of .70 for OS and .57 for PFS. The overall one-sided significance level of .05 is split to .04 for OS and .01 for PFS, with power 78% for OS and 80% for PFS. A safety evaluation for pneumonitis will take place after the first 30 patients reach the 12 weeks follow-up on the experimental arm. Safety will be monitored by the Independent Data Monitoring Committee every 3 months. Translational research will be done on formalin-fixed, paraffin-embedded tumour tissue, PBMCs, whole blood and serum samples at the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland. Up to April 2016, 7 pts have been randomised, and enrolment is ongoing. Clinical trial identification: EudraCT number: 2013-002609-78
Legal entity responsible for the study: European Thoracic Oncology Platform ETOP
Funding: Bristol-Myers Squibb
Disclosure: S. Popat: Consultant to BMS. M. Reck: Honoraria for consultancy and lectures
from: Hoffmann-La Roche, Lilly, BMS,MSD, AstraZeneca, Boehringer-Ingelheim, Pfizer,
Celgene. All other authors have declared no conflicts of interest.
背景
Checkmate032试验的初步结果显示两种免疫检查点抑制剂nivolumab（抗PD1单克隆IgG1抗体）联合ipilimumab（抗CTLA4单克隆IgG1抗体）治疗既往接受过治疗的进展期小细胞肺癌患者获得了高达31%的客观反应率及48%的一年总生存。本研究针对已经接受了标准化疗、胸部放疗以及预防性颅脑照射的局限期小细胞肺癌的患者，该研究意在研究此治疗是否可作为巩固治疗选择。
试验设计
STIMULI是一项开放性、随机、双臂、II期临床试验。入组条件为I-IIIB期未接受过治疗且器官功能及肺功能良好的局限期小细胞肺癌患者，要求患者既往无自身免疫性疾病。所有的患者接受高分割或传统分割的胸部放疗同时联合4周期的顺铂/卡铂+依托泊苷，之后进行颅脑预防性照射。在完成上述治疗后，未进展的患者1:1随机分成两组，治疗组（诱导及维持治疗）及观察组。诱导治疗为3周的ipilimumab 3mg/kg联合nivolumab 1mg/kg，随后为不超过12个月的nivolumab 240mg每两周使用一次维持治疗。主要研究终点为无进展生存期（PFS）及总生存（OS）。次要研究终点为客观反应率（ORR），疾病进展时间及疾病耐受时间。在标准治疗期计划入组325人，这样可以保证260例患者可以进行随机分组，预计的风险比OS为0.7，PFS0.57。同时最初入组的试验组30例患者在治疗后12周随访时进行肺炎的安全性评估。安全性每三个月由独立数据监测委员会评估。患者的福尔马林固定的组织、石蜡包裹的组织、外周血单核细胞、全血及血清样本来源于瑞士佛多斯大学医学中心，所有样本用于转化研究。至2016年4月，7例患者已经被随机分组，该试验现在仍在入组阶段。
1431TiP：A Phase III study of atezolizumab with carboplatin plus etoposide in patients with extensive-stage small cell lung cancer (IMpower133)
IMpower133: atezolizumab联合化疗（卡铂+依托泊苷）治疗广泛期小细胞肺癌的III期临床研究
Background: The current standard first-line treatment for the majority of patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) is platinum-based chemotherapy with etoposide. Despite initial response rates ranging from 50% to 70%, median survival remains < 1 year. Atezolizumab (atezo) is an anti-PD-L1 agent that inhibits PD-L1/PD-1 signaling and restores anti-tumor T-cell activity. Atezo monotherapy has shown promising efficacy and safety in many tumor types, including SCLC (ORR by RECIST v1.1, 6% [1/17]; ORR by irRC, 24% [4/17]; Sequist et al. ESMO 2016, pending). In addition, pre-clinical and Phase I data indicate that atezo given with platinum-based chemotherapy in non-small cell lung cancer may be synergistic and results in durable responses that may translate into improved survival. (Camidge et al. WCLC 2015). Together, these findings provide a rationale to assess whether atezo combined with carboplatin + etoposide (CE) results in improved survival vs CE alone in the first-line treatment of ES-SCLC.
Trial design: IMpower133 is a randomized, Phase III, multicenter, double-blinded, placebo-controlled study evaluating the efficacy and safety of atezo + CE vs placebo + CE in treatment-naive pts with ES-SCLC. Pts will be enrolled regardless of PD-L1 expression status. Pts with untreated CNS metastases, autoimmune disease or prior anti-cancer therapy for ES-SCLC will be excluded. Eligible pts will be stratified by sex, ECOG PS and presence of brain metastases, and randomized 1:1 to treatment arms. The induction phase of the study will consist of four 21-day cycles of atezo (1200 mg IV) or placebo with CE (C AUC 5, day 1 + E 100 mg/m2, days 1-3) followed by maintenance atezo or placebo until PD per RECIST v1.1. Treatment can be continued until persistent radiographic PD or symptomatic deterioration. Investigator-assessed PFS per RECIST v1.1 and OS are the co-primary endpoints. Secondary endpoints include ORR, DOR, quality of life, safety/tolerability and pharmacokinetics. Approximately 400 pts will be enrolled globally.
Clinical trial identification: NCT: available on poster
Legal entity responsible for the study: F. Hoffmann-La Roche Ltd
Funding: F. Hoffmann-La Roche Ltd
背景
目前大部分广泛期小细胞肺癌的一线标准治疗方案为以铂为基础联合依托泊苷的化疗。最初的反应率为50%-70%，但是中位生存期仍小于一年。Atezolizumab（atezo）为抗PD-L1抗体，其可抑制PD-L1/PD-1信号通路并恢复抗肿瘤T细胞的活性。Atezo单药治疗在很多种类型肿瘤治疗中都显示出了良好的疗效及安全性，包括小细胞肺癌（RECIST v1.1 ORR 6%，irRC ORR 24%）。临床前试验及I期临床试验数据显示atezo与铂类为基础的化疗联合治疗非小细胞肺癌有协同效果，同时可以获得持久的反应，这种持久的反应也许可以转化为生存期的延长。所有的这些数据是本试验设计的理论基础。因此本研究旨在观察广泛期小细胞肺癌一线接受atezo与化疗（卡铂C+依托泊苷E）联合治疗对比单纯化疗（CE）是否有生存期差异。
试验设计
IMpower133是一项随机、III期、多中心、双盲、安慰剂作为对照组的临床研究，评估atezo+CE对比安慰剂+CE治疗既往未接受过治疗的广泛期小细胞肺癌患者的安全性及疗效。患者入组将不考虑PD-L1的表达状态。排除条件为患者有未治疗的中枢神经系统转移、自身免疫疾病或既往接受过抗肿瘤治疗。符合条件的患者根据性别、ECOG、 PS及是否有脑转移分层并随机1:1分为两组。诱导治疗期包括atezo（1200mg IV）或安慰剂联合CE（C AUC 5 d1，E 100mg/m^2 d1-3），随后接受atezo或安慰剂维持治疗直至达到RECIST v1.1标准的病情进展。持续放射线评估PD或有症状的恶化着继续维持治疗。主要研究终点为研究者评估的PFS(RECIST v1.1)和OS。次要研究终点包括ORR、DOR、生活质量、安全性/耐受性及药代动力学。在全球范围内预计入组400人。
1432TiP：Immune surveillance reactivation to improve overall survival in small cell lung cancer (SCLC): The randomized IMPULSE study
Background: The immune surveillance reactivator lefitolimod (MGN1703), a DNA-based Toll-like receptor 9 (TLR9) agonist, was compared to placebo in metastatic CRC (mCRC) patients with disease control after standard induction chemotherapy in the double-blind randomized phase 2 IMPACT study. Lefitolimod showed a superior effect over placebo in exploratory analyses of pretreatment characteristics that identified patients most likely to benefit from lefitolimod. A study in small cell lung cancer (SCLC) patients, IMPULSE, was designed to confirm this preliminary evidence of efficacy in a new, high-mortality-and-unmet-need indication.
Trial design: Trial characteristics: IMPULSE is a randomized, international, multicenter, open-label trial to assess the effect of TLR9-mediated immune surveillance reactivation on overall survival (OS) in extensive-disease (ED) SCLC patients. Secondary endpoints include PFS, response rates, safety, and quality of life (QOL). The baseline stratification factors neuron-specific enolase (NSE) and activated NKT cells are prospectively assessed. 103 patients with objective tumor response following 4 cycles of platinum-based first-line induction therapy were randomized to receive either lefitolimod switch-maintenance therapy or local standard of care in a 3:2 ratio. Upon relapse, patients are receiving appropriate second-line therapy. All patients take part in a comprehensive immune monitoring plan that will evaluate cytokines and chemokines in serum, and the activation status of various immune cell populations. Demographic characteristics: Out of 103 patients, 62 patients were allocated to the treatment arm; 41 to standard of care (control). Median age was 63 years (MGN1703) and 64 years (control). Male/female distribution was 39/22 and 29/12, respectively. Distribution of baseline stratification factors NKT activation (≧3.5%/ < 3.5%) between treatment and control arms was 41/20 and 26/15, for NSE levels (>20/≦20) 11/50 and 8/33, respectively. The figures show that patients have been adequately distributed and balanced between the two treatment arms.
Clinical trial identification: 2013-003503-19
Legal entity responsible for the study: MOLOGEN AG
Funding: MOLOGEN AG
Disclosure: R. Carter: Employee at MOLOGEN AG. All other authors have declared
no conflicts of interest.
随机IMPULSE研究：免疫监视再激活是否可提高小细胞肺癌总生存期
背景
免疫监视再激活剂Lefitolimod（MGN1703）为一种DNA为基础的Toll样受体9激活剂。II期随机双盲IMPACT研究中该药物用于已经接受过标准化疗的转移性结直肠癌的治疗，结果显示lefitolimod比安慰剂组效果更好。根据实验室检查指标哪类患者最可能获益于lefitolimod的研究中显示lefitolimod优于安慰剂组。IMPULSE研究设计为观察lefitolimo治疗小细胞肺癌的疗效。
试验设计
试验特征：IMPULSE为随机国际多中心开放性试验，旨在评估TLR9介导的免疫监视再激活剂治疗广泛期小细胞肺癌对总生存期的影响。次要研究终点为PFS、反应率、安全性及生活质量。基础分层因素为NSE以及激活的NKT细胞。在接受完4个周期以铂类为基础的一线化疗后，可评价客观疗效的103者随机接受lefitolimod转至维持治疗或局部标准治疗，这两部分的患者比例为3:2.复发的患者接受适当的二线治疗。所有的患者都接受全面的免疫状态监控，包括检测血清中细胞因子和趋化因子以及多种免疫细胞的激活状态。
人口学特征：
103例患者中62例进入治疗组，41例接受标准治疗（对照组）。中位年龄为63岁（MGN1703组），对照组64岁。男性/女性分布两组分别为39/22,29/12。基础分层因素NKT激活状态分为≥3.5%组及＜3.5%组，治疗组患者分布比例分别为41/20, 对照组分布比例为26/15。NSE水平以20为分界，＞20组及≤20组，治疗组患者比例为11/50，对照组患者比例为8/33。以上数据分布显示两组患者的分布是均衡的。
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