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复发性实体瘤儿童和年轻人的I期剂量/毒性试验，使用90Y-DOTA-tyr3-Octreotide （90Y-DOTATOC）靶向肿瘤细胞上表达的生长抑素受体2型（sst2）。使用111In-DTPA-Octreotide （Octreoscan）作为90Y-DOTATOC的替代物筛选潜在受试者的肿瘤sst2表达。未观察到剂量限制性毒性；此外，我们观察到在先前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患儿中，30%的部分缓解，24%的最小缓解和24%的疾病稳定的极好的缓解率。该试验的结果在2008年美国临床肿瘤学会会议上与其他儿童一期试验一起公布。我们使用90Y-DOTATOC进行分子靶向肽放疗的试验是儿科I期试验中唯一一项显示完全、部分或最小反应的试验。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90Y-DOTATOC是一种有效的治疗药物，适用于通过Octreoscan检测到表达sst2的神经母细胞瘤和神经内分泌肿瘤的儿童和年轻人。我们还将验证13-顺式维甲酸（cisRA）可以增强90Y-DOTATOC对表达sst2的复发或难治实体瘤的疗效的假设。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sst2的表达。这些有希望的观察结果为II期试验的设计提供了理论依据，该试验随机比较90Y-DOTATOC加或不加cisRA治疗患有神经母细胞瘤或神经内分泌肿瘤的儿童和年轻人。I期试验基于90Y-DOTATOC的固定剂量，将对肾脏的辐射剂量限制在<21Gy。一个重要的警告是，这个肾辐射剂量是根据90Y- DOTATOC的外部束辐射限制来选择的，90Y- DOTATOC是一种放射性药物，通过静脉给药，直接和选择性地向肿瘤细胞传递内部辐射。在这项II期试验中，我们还计划验证个体化剂量法将提供更准确的肾脏放射剂量估计，并使我们能够在增加肿瘤剂量的同时仍将每个受试者的肾脏剂量限制在23 Gy的安全水平。考虑到I期试验有希望的结果，即极好的反应率，没有剂量限制性毒性；我们的新数据显示cisRA介导sst2上调；以及来自5名I期试验受试者的新的个体化肾剂量学数据，我们建议在患有sst2阳性神经母细胞瘤或神经内分泌肿瘤的儿童和年轻人中进行90y - dota -tyr3-奥曲肽加或不加13-顺式维甲酸的随机II期试验。我们将采用个体化剂量法向肿瘤提供最大允许辐射剂量，同时将肾脏辐射剂量限制在23Gy。

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.