Targeted Radiotherapy with 90Y-BC8 Monclonal Antibody, Fludarabine and TBI Follow

90Y-BC8 单克隆抗体、氟达拉滨和 TBI 靶向放射治疗

基本信息

批准号：
8038924
负责人：
WILLIAM I BENSINGER
金额：
$ 35.26万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-09 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8038924
关键词：
90Y Address Adopted Affinity Age Allogenic Allografting Antibodies Autologous Autologous Bone Marrow Transplantation Blood Cells Bone Marrow Bortezomib Cells Combination Drug Therapy Dexamethasone Disease Disease Progression Disease Resistance Disease remission Disease-Free Survival Disorder by Site Dose Drug Combinations Future Goals Immunologics Isotopes Kidney Length Leukocytes Liver Lung Maintenance Therapy Malignant Neoplasms Marrow Maximum Tolerated Dose Multiple Myeloma Myeloid Leukemia Myeloproliferative disease No Evidence of Disease Organ Outcome PTPRC gene Patients Phase II Clinical Trials Prior Therapy Probability Progression-Free Survivals Radiation Radioactive Recurrence Regimen Relapse Residual state Resistance Safety Siblings Site Spleen Staging Stem cell transplant Stem cells Survival Rate Targeted Radiotherapy Technology Testing Thalidomide Time Tissues Transfusion Transplant Recipients Transplantation Treatment Failure Treatment Protocols Whole-Body Irradiation bone chemotherapy conventional therapy design dosimetry fludarabine improved innovation lenalidomide leukemia mortality neoplastic cell novel older patient phase 1 study prospective purge randomized trial response trial comparing tumor

项目摘要

DESCRIPTION (provided by applicant): Important progress has been made in the treatment of patients with multiple myeloma (MM). Randomized trials of autologous stem cell transplant (ASCT) v. conventional therapy alone have demonstrated significant improvements in survival. Novel drug combinations of thalidomide, lenalidomide and bortezomib plus ASCT have further improved progression-free survival compared older induction regimens. Nevertheless few patients with MM survive without disease progression beyond 10 years. Strategies such as double ASCT, maintenance therapy after ASCT or an allogeneic transplant after ASCT are being studied as ways to improve outcomes. Allogeneic stem cell transplant (allo SCT) provides a tumor-free graft and an immunologic, graft-versus- myeloma effect. Myeloablative allo SCT for MM is associated with a 15-30% probability of disease free survival extending beyond 10 years, the best evidence for cure. Myeloablative allo SCT is, however, historically associated with high transplant related mortality (TRM) of 30-50%. Less intensive, nonmyeloablative allo SCT has been adopted which can reduce mortality to 15-20%, but to be successful, this approach requires that patients with MM receive cytoreductive therapy usually with ASCT, prior to the allo SCT. Even after a tandem auto-allo SCT, however, relapses remain the principal cause of treatment failure. Thus, there is a critical need for improved ways to provide better eradication of residual myeloma cells in the bone marrow. We have shown that 131I-anti-CD45 (BC8) Ab can deliver at least 2-3-fold more radiation to marrow, spleen and sites of leukemia than to any normal organ. We have further shown that high-dose 131I-BC8 Ab can be safely combined with a non-myeloablative regimen in older patients with myeloid malignancies. While CD45 is not widely expressed on the tumor cells of patients with MM, the broad expression of CD45 on all other leukocytes will allow effective targeting to marrow, the principal disease site in MM. Although 131I has been highly successful with regard to delivering targeted radiotherapy, concerns about safety and the transportability of this technology due to high gamma emissions of 131I and the relatively low ss energy of 131I have prompted a shift in strategy to the use of a 90Y-BC8 Ab conjugate for trials in multiple myeloma. 90Y with its lack of gamma emissions, higher ss energy and natural affinity for bone, should be a better isotope for targeting marrow. We will perform dosimetry testing with 111In-BC8 Ab, to establish that more CD45 is targeted to marrow than non-target tissues such as liver, lung and kidneys. Patients will next receive an ablative dose of 90Y-BC8, followed by a period for isotope decay, then the administration of fludarabine 90 mg/m2, external TBI 200 cGY and allo SCT from an HLA matched sibling or unrelated donor. The treatment protocol will involve a 2-stage dose escalation of isotope in patients designed to determine the maximum tolerated dose of 90Y anti-CD45, when combined with fludarabine and TBI in patients with MM receiving allo SCT. Adding marrow targeted radiation to a nonmyeloablative allo-SCT regimen should increase remissions and improve survival. PUBLIC HEALTH RELEVANCE: Multiple myeloma, a fatal form of cancer of the bone marrow, is usually treated with chemotherapy, radiation, in regular doses or very high doses, followed by re-transfusion of blood cells from the patient (autologous bone marrow transplant). Although remissions (no evidence of disease) can be obtained for some length of time, patients eventually relapse (recurrence of disease). In some cases blood cells from a donor can be used to perform an allogeneic transplant which may produce longer remissions. This study will test whether the addition of a radioactive antibody to target marrow can be done safely and increase remissions.

描述（由申请人提供）：多发性骨髓瘤（MM）患者的治疗已取得重要进展。自体干细胞移植（ASCT）与单独传统疗法的随机试验已证明生存率显着改善。与旧的诱导方案相比，沙利度胺、来那度胺和硼替佐米加 ASCT 的新型药物组合进一步改善了无进展生存期。然而，很少有 MM 患者能够存活超过 10 年而不发生疾病进展。正在研究诸如双 ASCT、ASCT 后维持治疗或 ASCT 后同种异体移植等策略来改善结果。同种异体干细胞移植（allo SCT）提供无肿瘤移植物和免疫学移植物抗骨髓瘤效应。 MM 的清髓性同种异体 SCT 与 15-30% 的概率无病生存期延长超过 10 年有关，这是治愈的最佳证据。然而，清髓性同种异体 SCT 历史上与 30-50% 的高移植相关死亡率 (TRM) 有关。强度较低的非清髓性同种异体 SCT 已被采用，可将死亡率降低至 15-20%，但为了取得成功，这种方法要求 MM 患者在异体 SCT 之前通常接受 ASCT 细胞减灭治疗。然而，即使在串联自体异体干细胞移植之后，复发仍然是治疗失败的主要原因。因此，迫切需要改进的方法来更好地根除骨髓中残留的骨髓瘤细胞。我们已经证明，131I-抗 CD45 (BC8) Ab 可以向骨髓、脾脏和白血病部位输送比任何正常器官至少多 2-3 倍的辐射。我们进一步表明，对于患有骨髓恶性肿瘤的老年患者，高剂量 131I-BC8 Ab 可以安全地与非清髓治疗方案联合使用。虽然 CD45 并未在 MM 患者的肿瘤细胞上广泛表达，但 CD45 在所有其他白细胞上的广泛表达将允许有效靶向骨髓（MM 的主要疾病部位）。尽管 131I 在提供靶向放射治疗方面取得了巨大成功，但由于 131I 的高伽马发射和 131I 相对较低的 ss 能量，对该技术的安全性和可运输性的担忧促使战略转向使用 90Y-用于多发性骨髓瘤试验的 BC8 Ab 缀合物。 90Y 缺乏伽马发射、更高的 ss 能量和对骨的天然亲和力，应该是一种更好的骨髓靶向同位素。我们将使用 111In-BC8 Ab 进行剂量测定测试，以确定更多的 CD45 靶向骨髓而不是肝、肺和肾等非靶组织。接下来，患者将接受 90Y-BC8 消融剂量，随后是同位素衰变期，然后给予氟达拉滨 90 mg/m2、外部 TBI 200 cGY 和来自 HLA 匹配的兄弟姐妹或无关供体的同种异体 SCT。该治疗方案将涉及对患者进行两阶段同位素剂量递增，旨在确定 90Y 抗 CD45 与氟达拉滨和 TBI 联合用于接受异体 SCT 的 MM 患者时的最大耐受剂量。在非清髓性异基因 SCT 方案中加入骨髓靶向放疗应可增加缓解并提高生存率。公共卫生相关性：多发性骨髓瘤是一种致命的骨髓癌，通常采用常规剂量或极高剂量的化疗、放疗进行治疗，然后重新输注患者的血细胞（自体骨髓移植）。尽管可以在一段时间内获得缓解（没有疾病的证据），但患者最终会复发（疾病复发）。在某些情况下，来自捐赠者的血细胞可用于进行同种异体移植，这可能会产生更长的缓解期。这项研究将测试是否可以安全地向靶骨髓添加放射性抗体并增加缓解。