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

90Y-DOTA-tyr3-奥曲肽视黄酸儿童剂量测定指导 II 期试验

基本信息

批准号：
7749337
负责人：
M. Sue O'Dorisio
金额：
$ 27.1万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7749337
关键词：
90Y Accounting American Society of Clinical Oncology Biopsy Biopsy Specimen Blood specimen Brain Neoplasms Child Childhood Clinical Trials Design Data Diagnosis Diagnostic Discipline of Nuclear Medicine Dose Dose-Limiting Effectiveness External Beam Radiation Therapy Formalin Goals Image Immunohistochemistry In 111 Pentetreotide Individual Infusion procedures Isotretinoin Kidney Laboratories Measures Mediating Neuroblastoma Neuroendocrine Tumors Octreotide Paraffin Embedding Patients Peptides Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Radiation Radiation therapy Radioactive Radiolabeled Radiopharmaceuticals Randomized Randomized Controlled Clinical Trials Recurrence Refractory Retinoic Acid Receptor Safety Solid Neoplasm Somatostatin Somatostatin Receptor Stable Disease Targeted Radiotherapy Testing Therapeutic Therapeutic Agents Time Toxic effect Tretinoin Up-Regulation base design dosimetry efficacy trial improved internal radiation kidney imaging meetings neoplastic cell partial response public health relevance radiotracer receptor expression response somatostatin receptor 2 tumor tumor progression young adult

项目摘要

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.

描述（由申请人提供）：我们刚刚完成了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，使用 90Y-DOTA-tyr3-奥曲肽 (90Y-DOTATOC) 来靶向 2 型生长抑素受体 (sst2)表达于肿瘤细胞上。使用 111In-DTPA-奥曲肽 (Octreoscan) 作为 90Y-DOTATOC 的替代品，筛选潜在受试者的 sst2 肿瘤表达。未观察到剂量限制性毒性；此外，我们观察到，在先前的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，我们观察到了良好的缓解率，部分缓解率为 30%，最小缓解率为 24%，疾病稳定为 24%。该试验的结果与其他针对儿童的 I 期试验一起在 2008 年美国临床肿瘤学会会议上公布。我们使用 90Y-DOTATOC 进行分子靶向肽放射治疗的试验是唯一一项显示出完全、部分或最小缓解的儿科 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，以检验我们的假设，即 90Y-DOTATOC 是一种有效治疗儿童和年轻人的神经母细胞瘤和神经内分泌肿瘤（经 Octreoscan 测定）表达 sst2 的药物。我们还将测试以下假设：13-顺式视黄酸 (cisRA) 可以增强 90Y-DOTATOC 在表达 sst2 的复发性或难治性实体瘤中的疗效。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基础，即对患有神经母细胞瘤或神经内分泌肿瘤的儿童和年轻人进行 90Y-DOTATOC 联合或不联合 cisRA 的随机比较。 I 期试验基于 90Y-DOTATOC 的固定剂量，将肾脏的辐射剂量限制在 <21Gy。一个重要的警告是，该肾脏辐射剂量是使用 90Y-DOTATOC 的外部束辐射限制来选择的，90Y-DOTATOC 是一种通过静脉注射直接选择性地向肿瘤细胞传递内部辐射的放射性药物。在这项 II 期试验中，我们还计划检验以下假设：个体化剂量测定将提供更准确的肾脏辐射剂量估计，使我们能够增加肿瘤剂量，同时仍将每个受试者的肾脏剂量限制在 23 Gy 的安全水平。考虑到第一阶段试验的可喜结果，即良好的反应率且无剂量限制性毒性；我们的新数据证明 cisRA 介导 sst2 上调；以及来自 I 期试验中 5 名受试者的新的个体化肾脏剂量测定数据，我们建议对患有 sst2 阳性神经母细胞瘤的儿童和年轻人进行一项随机 II 期试验，使用 90Y-DOTA-tyr3-奥曲肽（含或不含 13-顺式视黄酸）或神经内分泌肿瘤。我们将采用个体化剂量测定来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。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接受使用放射性生长抑素类似药物（奥曲肽）进行靶向放射治疗，该药物可寻找表达生长抑素受体的肿瘤细胞。一半的患者还将接受视黄酸治疗，以观察这是否可以提高放射性标记的奥曲肽的有效性。将进行核医学测试以确定可以安全地给予多少放射性奥曲肽而不会对肾脏产生毒性。