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) 患者的重要组成部分不幸的是，老年患者或患有合并症的患者不能耐受 TBI 相关的高风险急性白血病。这些患者对降低强度的预处理方案的耐受性更好，但与毒性有关。因此，当务之急是开发创新的有针对性的器官保留。放射治疗的形式，例如肿瘤特异性放射免疫治疗（RIT）和全骨髓照射（TMLI），允许对疾病部位进行安全的剂量强化，同时减少毒性，特别是对于老年患者或那些 TMLI 使用 CT 图像将辐射瞄准用户定义的目标区域（即骨髓）。我们的团队之前曾报道过在引导调强放射治疗中添加 12 Gy TMLI。氟达拉滨 (flu) 和美法仑 (mel) 的降低强度调理方案是可行的，且毒性可接受与单独使用 Flu-mel 类似，并且令人鼓舞的 2 年 OS 和 RFS 分别为 54% 和 49% (NCT00544466)。然而，由于粘膜炎，对于 60 岁以上的患者，流感/梅尔的 TMLI 剂量递增具有挑战性，这表明提供与 TMLI 互补的其他形式的靶向放疗可能对该患者有益鉴于 CD25 在急性白血病亚群中的高表达，CD25 可能是理想的 RIT 靶点。与低存活率和白血病干细胞的优先表达有关，我们已提交了 IND 申请。 (115386) 钇 90 (90Y) 标记的 DOTA 抗 CD25 巴利昔单抗，最近完成了两个 I 期临床试验该药物联合 BEAM 在霍奇金病 (NCT01476839) 和非霍奇金病患者中进行的试验淋巴瘤 (NCT02342782) 接受自体 HCT 在此，我们建议将抗 CD25 RIT 添加到我们的研究中。为复发/难治性 (R/R) CD25- 患者建立了 TMLI 12 Gy/flu/mel 预处理方案患有急性白血病的患者> 60岁，我们勇敢地将剂量增加到90Y-。在建立同种异体 HCT TMLI 12 Gy 方案前一周给予 DOTA-巴利昔单抗 RIT Flu-mel 是可行的，并且具有可接受的毒性和非复发死亡率 (NRM)，并且我们将能够定义 RIT 剂量以进行更大规模的疗效试验。在我们的目标 1 中，我们将进行描述。安全性并确定 90Y-巴利昔单抗与 TMLI-flu-mel 联合使用时的适当剂量（固定剂量 12 Gy）的 60 岁以上接受 alloHCT 治疗 R/R 急性白血病的患者。定义 90Y-巴利昔单抗的最大耐受剂量 (MTD) 和推荐的 2 期剂量 (RP2D)。具体目标 2 我们将进行相关研究，调查生物分布（BD）和 90Y-巴利昔单抗的药代动力学 (PK) 该试验将作为一种新方法的原理证明。结合两种互补形式的靶向放射治疗，并以 Waldmann，但利用市售抗体（巴利昔单抗），允许进展到多中心审判。