背景:患有中枢神经系统(CNS肿瘤)复发的儿童,神经母细胞瘤,肉瘤,和其他罕见的实体瘤面临不良预后。这项前瞻性临床试验研究了将肿瘤样本的基因组和转录组学分析与分子肿瘤委员会(MTB)方法相结合的可行性,为复发性/难治性实体瘤儿童做出实时治疗决策。
方法:受试者分为三个层次:1层复发/难治性神经母细胞瘤;2层复发/难治性CNS肿瘤;和3层复发/难治性罕见实体瘤。肿瘤样本进行肿瘤/正常全外显子组(WES)和肿瘤全转录组(WTS)测序,基因组数据被用于多机构MTB,以做出实时治疗决策。MTB推荐的计划允许多达4种药物的组合。通过完成基因组测序的时间来衡量可行性,MTB审查和开始治疗。在每两个周期后使用实体瘤中的反应评估标准(RECIST)评估反应。患者临床获益由CR的总和计算,PR,SD,和NED受试者除以完全反应(CR)的总和,部分响应(PR),稳定的疾病(SD),没有疾病证据(NED),和进行性疾病(PD)受试者。将3级及以上相关和意外不良事件(AE)制成表格用于安全性评价。
结果:共纳入186名符合条件的患者,其中144名安全性可评价,124名反应可评价。从活检到开始MTB推荐的联合治疗的平均天数为38天。所有受试者中有65%的患者获益,67%的神经母细胞瘤受试者,73%的中枢神经系统肿瘤受试者,和60%的罕见肿瘤受试者。该试验期间使用的MGT药物的相关毒性几乎不高于预期,提示使用这种选择联合靶向治疗方法的安全性。
结论:该试验证明了可行性,安全,以及综合测序模型的有效性,以指导任何复发/难治性实体恶性肿瘤患者的个性化治疗。个性化治疗耐受性良好,在这些经过大量预处理的人群中,65%的临床获益率表明,这种治疗策略可能是复发和难治性儿科癌症的有效选择.
背景:ClinicalTrials.gov,NCT02162732。2014年6月11日登记。
Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make real‑time treatment decisions for children with relapsed/refractory solid tumors.
Subjects were divided into three strata: stratum 1-relapsed/refractory neuroblastoma; stratum 2-relapsed/refractory CNS tumors; and stratum 3-relapsed/refractory rare solid tumors. Tumor samples were sent for tumor/normal whole-exome (WES) and tumor whole-transcriptome (WTS) sequencing, and the genomic data were used in a multi-institutional MTB to make real‑time treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every two cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient clinical benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of complete response (CR), partial response (PR), stable disease (SD), no evidence of disease (NED), and progressive disease (PD) subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation.
A total of 186 eligible patients were enrolled with 144 evaluable for safety and 124 evaluable for response. The average number of days from biopsy to initiation of the MTB-recommended combination therapy was 38 days. Patient benefit was exhibited in 65% of all subjects, 67% of neuroblastoma subjects, 73% of CNS tumor subjects, and 60% of rare tumor subjects. There was little associated toxicity above that expected for the MGT drugs used during this trial, suggestive of the safety of utilizing this method of selecting combination targeted therapy.
This trial demonstrated the feasibility, safety, and efficacy of a comprehensive sequencing model to guide personalized therapy for patients with any relapsed/refractory solid malignancy. Personalized therapy was well tolerated, and the clinical benefit rate of 65% in these heavily pretreated populations suggests that this treatment strategy could be an effective option for relapsed and refractory pediatric cancers.
ClinicalTrials.gov, NCT02162732. Prospectively registered on June 11, 2014.