Evaluation of the Safety and Benefit of Phase I Oncology Trials for Patients With Primary CNS Tumors.
Evaluation of the Safety and Benefit of Phase I Oncology Trials for Patients With Primary CNS Tumors.
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DOI：
10.1200/jco.2015.61.1525
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发表时间：
2015-10-01
期刊：
影响因子：
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通讯作者：
Wen PY
中科院分区：
文献类型：
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作者：
Gounder MM;Nayak L;Sahebjam S;Muzikansky A;Sanchez AJ;Desideri S;Ye X;Ivy SP;Nabors LB;Prados M;Grossman S;DeAngelis LM;Wen PY
高级别神经胶质瘤（HGG）患者经常被排除在首次人体实体瘤试验之外，因为预期预后不良、过度毒性、伴随药物相互作用和疗效差。我们对HGG患者中选择的单药I期研究的结局进行了分析。我们将结果与已发表的实体瘤研究的汇总分析进行了比较，这些研究使用了各种分子和细胞毒性药物作为单一药物或组合进行评价。对2000年至2008年入组成人脑肿瘤联盟单药、细胞毒性或分子药物试验的复发性HGG患者的个体记录进行基线特征、毒性、缓解和生存分析。我们的分析包括327例晚期难治性HGG患者，他们参加了8项涉及靶向分子（n = 5）和细胞毒性（n = 3）治疗的试验。入组时，患者的中位Karnofsky表现评分为90，中位年龄为52岁; 62%为男性，63%患有胶质母细胞瘤，既往全身化疗的中位次数为1次。基线实验室检查值在可接受范围内，符合合格性标准。患者参加研究的中位数为2个周期（范围，<1至56个周期），96%的患者可评价主要终点。在第1周期，≥ 3级非血液学毒性和≥ 4级血液学毒性分别为5%（565例不良事件中的28例）和0.9%（565例不良事件中的5例），其中66%发生在最高剂量水平。有1例死亡归因于药物。总体缓解率（完全缓解和部分缓解）为5.5%。中位无进展生存期和总生存期分别为1.8个月和6个月。符合标准合格标准的HGG患者可能是实体瘤I期研究的良好候选者，该研究采用单药分子或细胞毒性药物，在该人群中具有良好的临床前原理和药代动力学特性。
Patients with high-grade gliomas (HGG) are frequently excluded from first-in-human solid tumor trials because of perceived poor prognosis, excessive toxicities, concomitant drug interactions, and poor efficacy. We conducted an analysis of outcomes from select, single-agent phase I studies in patients with HGG. We compared outcomes to pooled analysis of published studies in solid tumors with various molecular and cytotoxic drugs evaluated as single agents or as combinations. Individual records of patients with recurrent HGG enrolled onto Adult Brain Tumor Consortium trials of single-agent, cytotoxic or molecular agents from 2000 to 2008 were analyzed for baseline characteristics, toxicities, responses, and survival. Our analysis included 327 patients with advanced, refractory HGG who were enrolled onto eight trials involving targeted molecular (n = 5) and cytotoxic (n = 3) therapies. At enrollment, patients had a median Karnofsky performance score of 90 and median age of 52 years; 62% were men, 63% had glioblastoma, and the median number of prior systemic chemotherapies was one. Baseline laboratory values were in an acceptable range to meet eligibility criteria. Patients were on the study for a median of two cycles (range, < one to 56 cycles), and 96% were evaluable for primary end points. During cycle 1, grade ≥ 3 nonhematologic and grade ≥ 4 hematologic toxicities were 5% (28 of 565 adverse events) and 0.9% (five of 565 adverse events), respectively, and 66% of these occurred at the highest dose level. There was one death attributed to drug. Overall response rate (complete and partial response) was 5.5%. Median progression-free and overall survival times were 1.8 and 6 months, respectively. Patients with HGG who meet standard eligibility criteria may be good candidates for solid tumor phase I studies with single-agent molecular or cytotoxic drugs with favorable preclinical rationale and pharmacokinetic properties in this population.