Anti-CD25 Radioimmunotherapy and Total Marrow Irradiation for Treatment of Relapsed and Refractory Acute Leukemia

抗CD25放射免疫治疗和全骨髓照射治疗复发难治性急性白血病

基本信息

批准号：
10576955
负责人：
JEFFREY Y WONG
金额：
$ 19.2万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576955
关键词：
90Y Acute Myelocytic Leukemia Acute leukemia Address Age Allogenic Antibodies Ara-C Area Autologous Biodistribution Blood specimen Bone Marrow Carmustine Circulation Cities Clinical Complementary therapies Correlative Study Cyclophosphamide Disease Dose Drug Kinetics Engraftment Esophagitis Etoposide Future Goals Hepatic Hodgkin Disease IL2RA gene In complete remission Incidence Intensity-Modulated Radiotherapy Kidney Label Leukemic Cell Lymphoblastic Leukemia Marrow Maximum Tolerated Dose Melphalan Methods Mucositis Multicenter Studies Multicenter Trials Non-Hodgkin&apos s Lymphoma Organ Patients Phase Positioning Attribute Radiation Radiation therapy Radioimmunotherapy Recommendation Refractory Regimen Relapse Reporting Safety Scanning Site Survival Rate Targeted Radiotherapy Testing Toxic effect Transplant Recipients Transplantation Conditioning VP 16 Whole-Body Irradiation Work X-Ray Computed Tomography appropriate dose basiliximab comorbidity conditioning design dosimetry efficacy trial experience first-in-human flu fludarabine graft vs host disease hematopoietic cell transplantation high risk image guided image guided radiation therapy innovation irradiation leukemia leukemic stem cell lymphoid irradiation mortality novel older patient patient population phase 1 study phase 2 study phase I trial phase II trial primary endpoint randomized trial sample collection secondary endpoint standard of care tumor

项目摘要

SUMMARY/ABSTRACT Total body irradiation (TBI) remains an essential part of hematopoietic cell transplantation (HCT) for patients with high risk acute leukemia. Unfortunately, older patients or those with comorbidities cannot tolerate TBI-related toxicities. Reduced intensity conditioning regimens are better tolerated by these patients but are associated with significant increase in relapse rate. Therefore, It is imperative to develop innovative targeted, organ sparing forms of radiotherapy, such as tumor-specific radioimmunotherapy (RIT) and total marrow irradiation (TMLI), to allow for safe dose intensification to disease sites while reducing toxicities, especially in older patients or those with comorbidities. TMLI targets radiation to user-defined target regions (i.e. bone marrow), using CT image guided intensity modulated radiotherapy. Our team has previously reported that adding 12 Gy TMLI to the reduced intensity conditioning regimen of fludarabine (flu) and melphalan (mel) is feasible with acceptable toxicity similar to flu-mel alone, and encouraging 2-year OS and RFS of 54% and 49%, respectively (NCT00544466). However, TMLI dose escalation with flu/mel in patients > 60 years old is challenging due to mucositis, suggesting that delivering other forms of targeted radiotherapy complementary to TMLI may be beneficial in this patient population. CD25 might be an ideal RIT target given its high expression in a subset of acute leukemias, association with low survival rates, and preferential expression by leukemia stem cells. We have filed an IND (115386) for yttrium-90 (90Y)-labeled-DOTA-anti-CD25 basiliximab and have recently completed two Phase I trials with this agent combined with BEAM in patients with Hodgkin’s (NCT01476839) and non-Hodgkin’s lymphoma (NCT02342782) undergoing autologous HCT. Here, we propose to add anti-CD25 RIT to our established conditioning regimen of TMLI 12 Gy/ flu/ mel for patients with relapsed/refractory (R/R) CD25- expressing acute leukemia who are > 60 years old. We hypothesize that the combination of dose escalated 90Y- DOTA-basiliximab RIT administered one week prior to an established allogeneic HCT regimen of TMLI 12 Gy- flu-mel is feasible and associated with acceptable toxicities and non-relapse mortality (NRM) rates, and that we will be able to define an RIT dose to carry forward into larger efficacy trials. In our aim 1, we are going to describe safety and establish appropriate dosing of 90Y-basiliximab when combined with TMLI-flu-mel (at the fixed dose of 12 Gy) in patients ≥ 60 years old undergoing alloHCT for R/R acute leukemia. Our primary objective is to define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of 90Y-basiliximab. In specific aim 2 we will conduct correlative studies investigating the biodistribution (BD) and pharmacokinetics (PK) of 90Y-basiliximab. This trial will serve as proof of principal for a novel method of combining two complementary forms of targeted radiotherapy and builds on the pioneering work of Waldmann, but utilizes the commercially available antibody (basiliximab), allowing for progression to a multi- center trial.

摘要/摘要全身照射（TBI）仍然是造血细胞移植（HCT）的重要组成部分高风险急性白血病。不幸的是，老年患者或合并症的患者无法忍受与TBI有关的毒性。这些患者可以更好地耐受强度调节方案，但与继电器率的显着增加。因此，必须开发创新的目标，组织较高的目标是放射疗法的形式，例如肿瘤特异性放射性疗法（RIT）和总骨髓照射（TMLI）在降低毒性的同时，尤其是在老年患者或那些的同时，可以安全剂量加强疾病部位合并症。 TMLI使用CT图像将辐射靶向用户定义的目标区域（即骨髓）指导强度调节放射疗法。我们的团队此前曾报告说，在氟达拉滨（Fludarabine）（流感）和Melphalan（Mel）的强度调节方案降低，可接受的毒性是可行的单独类似于流感摩尔，并鼓励2年OS和RF分别为54％和49％（NCT00544466）。然而，> 60岁的患者的TMLI剂量升级因粘膜炎而挑战，这表明将其他形式的靶向放射疗法完整性运送到TMLI可能对该患者有益人口。 CD25可能是理想的RIT目标，因为它在急性白血病的一部分中高表达，与低存活率相关，并通过白血病干细胞优选表达。我们已经提交了一个IND （115386）对于Yttrium-90（90Y） - 标记 - dota-anti-cd25 basiliximab，最近完成了两个I期I 该试剂与Hodgkin患者（NCT01476839）和非霍奇金（Non-Hodgkin）的患者进行试验。淋巴瘤（NCT02342782）接受自体HCT。在这里，我们建议将抗CD25 RIT添加到我们的复发/难治（R/R）CD25-的患者的TMLI 12 Gy/Flu/Melt的调节方案表达超过60岁的急性白血病。我们假设剂量的组合升级为90y- dota-basiliximab RIT在建立的TMLI的同种异体HCT方案前一周服用 Flu-Mel是可行的，并且与可接受的毒性和非释放死亡率（NRM）相关，并且我们将能够定义RIT剂量以进行更大的效率试验。在我们的目标1中，我们将描述与TMLI-FLU-MEL合并时，安全并建立适当剂量的90-Basiliximab（以固定剂量 R/R急性白血病患有AllOHCT的患者中，为12 Gy）。我们的主要目标是定义90y-basiliximab的最大耐受剂量（MTD）和建议的2期2剂量（RP2D）。在具体目的2我们将进行研究生物分布（BD）和 90y-basiliximab的药代动力学（PK）。该试验将作为一种新方法的委托人证明结合两种完整形式的有针对性放疗，并建立在开创性的工作基础上沃尔德曼（Waldmann），但利用了市售抗体（basiliximab）中心审判。