Anti-CD38 Radioimmunotherapy and Total Marrow Irradiation for Treatment of Relapsed and Refractory Acute Myelogenous Leukemia - SUMMARY/ABSTRACT Total body irradiation (TBI) remains an essential part of hematopoietic cell transplantation (HCT) for patients with high-risk acute myeloid leukemia (AML). Older patients or those with comorbidities cannot tolerate TBI- related toxicities. Reduced intensity conditioning (RIC) regimens are better tolerated but are associated with a significant increase in relapse rate. 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 disease sites (i.e. bone marrow), using intensity modulated radiotherapy. Our team has reported that adding 12 Gy TMLI to the RIC regimen of fludarabine (flu) and melphalan (mel) is feasible with acceptable toxicity similar to flu-mel alone and encouraging 5-year OS and RFS of 42% and 41%, respectively (NCT00544466), superior to existing strategies in the same population. However, TMLI dose escalation with flu/mel in patients > 60 years old is challenging due to mucositis, suggesting that delivering of other forms of targeted radiotherapy complementary to TMLI may be beneficial in this patient population. CD38 is an ideal RIT target given its high and frequent expression in AML. Alpha- emitter RIT or targeted alpha therapy (TAT) has the potential to further increase the therapeutic ratio and improve efficacy of RIT compared to beta- or gamma emitting radionuclides. Here, we propose to add anti- CD38 TAT to our established conditioning regimen of TMLI 12 Gy/ flu/ mel for patients with relapsed/refractory (R/R) AML who are > 60 years old. We hypothesize that the combination of dose escalated 225Ac-DOTA- daratumumab (Dara) 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 establish appropriate dosing of 225Ac-DOTA-Dara when combined with TMLI-flu-mel in patients ≥ 60 years old undergoing allogeneic hematopoietic cell transplantation for R/R AML. Our primary objective is to define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of 225Ac-DOTA-Dara. We will also conduct correlative studies investigating the biodistribution (BD) and pharmacokinetics (PK) of 225Ac-DOTA- Dara, and study changes on AML cells and immune environment before and after transplant associated with the addition of CD38-TAT to TMLI-flu-mel. Aim 2 focuses on preclinical studies in immune competent humanized CD38 transgenic mice (hCD38) to optimize CD38-TAT as a single agent for AML treatment to induce disease remission and minimize off-target toxicities. This trial will serve as proof of principle for a novel method of combining two complementary forms of targeted radiotherapy and utilizes commercially available antibody, allowing for progression to a multi-center trial.
