Phase 1b Study of Dulanermin (recombinant human Apo2L/TRAIL) in Combination With Paclitaxel, Carboplatin, and Bevacizumab in Patients With Advanced Non-Squamous Non-Small-Cell Lung Cancer
Phase 1b Study of Dulanermin (recombinant human Apo2L/TRAIL) in Combination With Paclitaxel, Carboplatin, and Bevacizumab in Patients With Advanced Non-Squamous Non-Small-Cell Lung Cancer
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DOI：
10.1200/jco.2009.25.4847
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发表时间：
2010-03-20
影响因子：
45.3
通讯作者：
Blackhall, Fiona
中科院分区：
文献类型：
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作者：
Soria, Jean-Charles;Smit, Egbert;Blackhall, Fiona
目的研究度兰明联合紫杉醇、卡铂和贝伐单抗治疗初治、非鳞癌、IIIb期(伴胸腔积液)/IV期或复发性非小细胞肺癌(NSCLC)患者的安全性、药代动力学(PK)和最大耐受量(MTD)。在这项1b期研究中，患者(n=24)在每21天周期的第1天接受度兰那明，然后以4或8 mg/kg/d连续5天或15或20 mg/kg/d连续2天给药。评估了剂量限制毒性(DLTS)、不良事件和抗双酚A抗体的发生率。记录每个代理的PK参数。结果24例患者接受了至少一个剂量的度那明加多氯联苯，每个治疗队列6人。没有DLT。未达到MTD，该药物组合耐受性良好。对于多氯联苯方案，治疗后出现的不良反应总体上与预期一致。度那明的不良反应为1/2级；未发生明显的肝毒性。多氯联苯对度兰那明的pk影响很小。1例确诊为完全应答，13例确诊为部分应答。总有效率为58%(95%可信区间，37~78)。中位无进展生存期为7.2个月(95%CI，4.7~10.3)。结论Dulanermin加PCb在该患者群体中耐受性良好，未发生DLTS，并显示出抗肿瘤活性。Dulanermin8 mg/kg/d，5天，20 mg/kg/d，每3周2天，与多氯联苯联合使用正在进行II期试验。
PurposeTo determine the safety, pharmacokinetics (PK), and maximum-tolerated dose (MTD) up to a prespecified target dose of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab (PCB) in patients with previously untreated, nonsquamous, stage IIIb (with pleural effusion)/IV or recurrent non-small-cell lung cancer (NSCLC).Patients and MethodsIn this phase 1b study, patients (n = 24) received PCB on day 1 of each 21-day cycle then dulanermin at 4 or 8 mg/kg/d for 5 consecutive days or 15 or 20 mg/kg/d for 2 consecutive days per assigned treatment cohort. Incidence of dose-limiting toxicities (DLTs), adverse events, and antidulanermin antibodies were assessed. PK parameters were recorded for each agent. Tumor response was measured by modified Response Evaluation Criteria in Solid Tumors.ResultsTwenty-four patients received at least one dose of dulanermin plus PCB, six in each treatment cohort. There were no DLTs. An MTD was not reached, and the drug combination was well tolerated. Treatment-emergent adverse events were generally as expected for the PCB regimen. Adverse events attributed to dulanermin were grade 1/2; no significant hepatotoxicity occurred. There was minimal impact of PCB on the PK of dulanermin. There was one confirmed complete response and 13 confirmed partial responses. The overall response rate was 58% (95% CI, 37 to 78). Median progression-free survival was 7.2 months (95% CI, 4.7 to 10.3).ConclusionDulanermin plus PCB was well tolerated with no occurrence of DLTs and demonstrated antitumor activity in this patient population. Dulanermin at 8 mg/kg/d for 5 days and 20 mg/kg/d for 2 days every 3 weeks in combination with PCB is being studied in a phase II trial.