Phase 0 carboplatin microdosing diagnostics trial

我们开发了一种名为PlatinDx的技术，该技术基于临床前数据，可以在癌症患者接受卡铂或顺铂治疗之前识别他们的化疗耐药性。PlatinDx利用加速器质谱仪(AMS)追踪治疗以下剂量的14C标记的卡铂，AMS对14C具有全摩尔(10-18摩尔)敏感性。我们假设，单次亚毒微量卡铂引起的DNA损伤可以预测患者的预后，如肿瘤缩小和存活。该项目的目标是定义适当的化学物质(治疗剂量-1/1)和 放射化学(胸部X光照射的几个百分比)微剂量成分，以建立程序的方案和收集初步临床数据。肺癌患者将在正常活检前几个小时接受14C-卡铂微量注射。DNA将从白细胞中分离出来，并留在肿瘤活检组织中。药物-DNA损伤水平将由AMS测量，并与肿瘤缩小、复发和副作用严重程度等结果进行比较。这些数据将与ERCC1表达和其他生物标记物进行比较，使用Response Genetics RT-PCR检测作为基准。由此产生的可行性数据将使SBIR第二阶段关键诊断研究的设计成为可能。

We developed a technology called PlatinDx that, based upon preclinical data, can potentially identify chemoresistance in cancer patients before they receive carboplatin or cisplatin therapy. PlatinDx utilizes tracing of subtherapeutic "microdoses" of 14C-labeled carboplatin with accelerator mass spectrometry (AMS), which has attomole (10-18 mole) sensitivity for 14C. We hypothesize that DNA damage caused by a single subtoxic microdose of carboplatin can predict patient outcomes such as tumor shrinkage and survival . The goal of the project is to define the appropriate chemical (-1 /1 DOth the therapeutic dose) and radiochemical (few percent of a chest x-ray exposure) microdose composition, to establish protocols for the procedure and to gather preliminary clinical data. Lung cancer patients will each receive a 14C-carboplatin microdose a few hours prior to normal biopsy. DNA will be isolated from white blood cells and left over tumor biopsy tissue. Drug-DNA damage levels will be measured by AMS and compared to outcomes such as tumor shrinkage, recurrence and severity of side effects. The data will be compared to ERCC1 expression and other biomarkers using the Response Genetics RT-PCR assay as a benchmark. The resulting feasibility data will allow the design of an SBIR Phase II pivotal diagnostic study.