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

• 批准号: 10435886
• 负责人: JEFFREY Y WONG
• 金额: $ 23.32万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435886
• 关键词: 90Y; Acute Myelocytic Leukemia; Acute leukemia; Address; Age; Allogenic; Antibodies; Ara-C; Area; Autologous; Biodistribution; Blood Circulation; Blood specimen; Bone Marrow; Carmustine; Cities; Clinical; Correlative Study; Cyclophosphamide; Disease; Dose; Drug Kinetics; 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' s Lymphoma; Organ; Patients; Phase; Positioning Attribute; Radiation; Radiation therapy; Radioimmunotherapy; 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; base; basiliximab; comorbidity; conditioning; design; dosimetry; efficacy trial; experience; first-in-human; 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

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.

总结/摘要 全身照射（TBI）仍然是造血细胞移植（HCT）的重要组成部分， 高危急性白血病不幸的是，老年患者或合并症患者不能耐受TBI相关的 毒性这些患者对降低强度预处理方案的耐受性更好，但与 复发率显著增加。因此，开展有针对性的、器官保留的创新治疗势在必行 放射治疗的形式，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，同时降低毒性，尤其是在老年患者或 合并症使用CT图像，TMLI将辐射靶向用户定义的靶区域（即骨髓） 引导调强放疗。我们的团队以前曾报道过，将12戈伊TMLI添加到 氟达拉滨（fludarabine，flu）和美法仑（melphalan，mel）的低强度预处理方案是可行的，毒性可接受 与单独使用flu-mel相似，2年OS和RFS分别为54%和49%（NCT 00544466）。 然而，在> 60岁的患者中，由于粘膜炎，TMLI剂量递增与流感/mel是具有挑战性的，这表明 给予其他形式的靶向放疗补充TMLI可能对该患者有益 人口CD 25可能是一个理想的RIT靶点，因为它在急性白血病的一个亚群中有高表达， 与低存活率和白血病干细胞的优先表达相关。我们已经申请了IND （115386）用于钇-90（90 Y）-标记-DOTA-抗-CD 25巴利昔单抗，最近完成了两项I期研究 在霍奇金淋巴瘤（NCT 01476839）和非霍奇金淋巴瘤患者中使用该药物联合BEAM的试验 淋巴瘤（NCT 02342782）接受自体HCT。在这里，我们建议将抗CD 25 RIT添加到我们的 复发性/难治性（R/R）CD 25- 60岁以上的急性白血病患者。我们假设剂量递增90年- DOTA-巴利昔单抗RIT在TMLI 12戈伊- flu-mel是可行的，并且与可接受的毒性和非复发死亡率（NRM）相关， 将能够确定一个RIT剂量进行到更大的疗效试验。在我们的目标1中，我们将描述 安全性，并确定90 Y-巴利昔单抗与TMLI-flu-mel联合给药时的适当剂量（固定剂量 的12戈伊）。我们的首要目标是 定义90 Y-巴利昔单抗的最大耐受剂量（MTD）和推荐II期剂量（RP 2D）。在 具体目标2，我们将进行相关研究，调查生物分布（BD）， 90 Y-巴利昔单抗的药代动力学（PK）。这项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，并建立在开创性的工作， Waldmann，但利用市售抗体（巴利昔单抗），允许进展为多- 中心试验。