Dosimetry Guided Phase II of 90Y-DOTA-tyr3-Octreotide + Retinoic Acid in Kids

描述（由申请人提供）：我们刚刚完成了一项针对患有复发性实体瘤的儿童和年轻人的I期剂量/毒性试验，该试验使用90 Y-DOTA-tyr 3-奥曲肽（90 Y-DOTATOC）靶向肿瘤细胞上表达的生长抑素受体2型（sst 2）。使用111 In-DTPA-奥曲肽（Octreoscan）作为90 Y-DOTATOC的替代物筛选潜在受试者的sst 2的肿瘤表达。未观察到剂量限制性毒性;此外，我们在既往一线和二线治疗方案失败的脑肿瘤、神经母细胞瘤和神经内分泌肿瘤儿童中观察到极好的缓解率，部分缓解率为30%，最小缓解率为24%，疾病稳定率为24%。这项试验的结果与其他儿童I期试验一起沿着在2008年美国临床肿瘤学会会议上公布。我们使用90 Y-DOTATOC进行的分子靶向肽放射治疗试验是唯一一项显示完全、部分或最小反应的儿科I期试验。这些令人鼓舞的I期结果促使我们设计了这项II期疗效试验，以验证我们的假设，即90 Y-DOTATOC是一种有效的治疗药物，用于治疗Octreoscan确定的表达sst 2的神经母细胞瘤和神经内分泌肿瘤的儿童和年轻人。我们还将检验13-顺式视黄酸（cisRA）可以增强90 Y-DOTATOC在表达sst 2的复发性或难治性实体瘤中的疗效的假设。我们实验室令人兴奋的新结果表明，cisRA增加了神经母细胞瘤和神经内分泌肿瘤细胞中sst 2的表达。这些有希望的观察结果为II期试验的设计提供了依据，该试验是在患有神经母细胞瘤或神经内分泌肿瘤的儿童和年轻人中随机比较90 Y-DOTATOC与或不与cisRA。I期试验基于90 Y-DOTATOC的固定剂量，将肾脏的辐射剂量限制在<21 Gy。一个重要的警告是，该肾辐射剂量是使用90 Y-DOTATOC的外部射束辐射限制来选择的，90 Y-DOTATOC是一种放射性药物，其静脉内施用以直接和选择性地向肿瘤细胞递送内部辐射。在这项II期试验中，我们还计划检验以下假设：个体化剂量测定法将提供更准确的肾脏放射剂量估计，并使我们能够增加肿瘤剂量，同时仍将每例受试者的肾脏剂量限制在23戈伊的安全水平。考虑到I期试验的有希望的结果，即，无剂量限制性毒性的优异响应率;我们的新数据表明cisRA介导的sst 2上调;以及I期试验中5名受试者的新的个体化肾脏剂量测定数据，我们建议进行一项随机的II期试验，90 Y-DOTA-tyr 3-奥曲肽与或不与13-顺式维甲酸在患有SST 2阳性神经母细胞瘤或神经内分泌肿瘤的儿童和年轻成人中的应用。我们将采用个体化的剂量学，将最大允许的辐射剂量输送到肿瘤，同时将肾脏辐射剂量限制在23 Gy。 公共卫生相关性：患有复发性神经母细胞瘤和神经内分泌肿瘤的儿童和年轻人将使用放射性生长抑素类似药物（奥曲肽）进行靶向放射治疗，该药物旨在寻找表达生长抑素受体的肿瘤细胞。一半的患者还将接受维甲酸治疗，以观察这是否能提高放射性标记奥曲肽的有效性。将进行核医学测试，以确定多少放射性奥曲肽可以安全地给予肾脏没有毒性。

DESCRIPTION (provided by applicant): We have just completed a Phase I dose/toxicity trial for children and young adults with recurrent solid tumors using 90Y-DOTA-tyr3-Octreotide (90Y-DOTATOC) to target the somatostatin receptor type 2 (sst2) expressed on tumor cells. Potential subjects were screened for tumor expression of sst2 using 111In-DTPA-Octreotide (Octreoscan) as a surrogate for 90Y-DOTATOC. No dose limiting toxicities were observed; furthermore, we observed an excellent response rate with 30% partial responses, 24% minimal responses, and 24% stable disease in children with brain tumors, neuroblastoma, and neuroendocrine tumors who had failed previous first and second line therapeutic options. Results of this trial were presented at the 2008 American Society for Clinical Oncology meeting along with other Phase I trials in children. Our trial of molecularly targeted peptide radiotherapy using 90Y-DOTATOC was the only one of the pediatric Phase I trials that demonstrated any complete, partial, or minimal responses. These encouraging Phase I results have prompted us to design this Phase II efficacy trial to test our hypothesis that 90Y-DOTATOC is an effective therapeutic agent in children and young adults with neuroblastoma and neuroendocrine tumors that express sst2 as determined by Octreoscan. We will also test the hypothesis that 13-cis retinoic acid (cisRA) can potentiate the efficacy of 90Y-DOTATOC in recurrent or refractory solid tumors that express sst2. Exciting new results in our laboratory demonstrate that cisRA increases expression of sst2 in both neuroblastoma and neuroendocrine tumor cells. These promising observations provide a rationale for design of the Phase II trial as a randomized comparison of 90Y-DOTATOC with or without cisRA in children and young adults with neuroblastoma or neuroendocrine tumors. The Phase I trial was based on fixed dosing of 90Y-DOTATOC, limiting the radiation dose to kidneys to <21Gy. An important caveat is that this renal radiation dose was chosen using external beam radiation limits for 90Y- DOTATOC, a radiopharmaceutical that is administered IV to deliver internal radiation directly and selectively to the tumor cells. In this Phase II trial, we also plan to test the hypothesis that individualized dosimetry will provide more accurate estimates of renal radiation dosing and enable us to increase the dose to tumor while still limiting the renal dose in each subject to a safe level of 23 Gy. Taking into account the promising results of the Phase I trial, namely, an excellent response rate with no dose limiting toxicities; our new data demonstrating cisRA mediated upregulation of sst2; and new, individualized renal dosimetry data from five subjects in the Phase I trial, we propose to conduct a randomized Phase II trial of 90Y-DOTA-tyr3-Octreotide with or without 13-cis retinoic acid in children and young adults with sst2 positive neuroblastoma or neuroendocrine tumors. We will employ individualized dosimetry to deliver the maximum allowable radiation dose to tumor while limiting renal radiation dose to 23Gy. PUBLIC HEALTH RELEVANCE: Children and young adults with recurrent neuroblastoma and neuroendocrine tumors will be given targeted radiotherapy with a radioactive somatostatin look-alike drug (Octreotide) that seeks out tumor cells which express the somatostatin receptor. Half of the patients will also receive retinoic acid to see if this improves the effectiveness of the radiolabeled Octreotide. A nuclear medicine test will be performed to determine how much radioactive Octreotide can be given safely without toxicity to the kidneys.