Trials in Progress: A Phase I/II Study of Venetoclax and Lintuzumab-Ac225 in Patients with Refractory or Relapsed AML

Context Resistance to venetoclax, a BCL2 inhibitor, has been shown to be mediated by co-expression of other BCL2 proteins, including BCLXL and MCL1. Therapeutic agents that reduce resistance to BCL2 inhibitors and themselves exhibit anti-tumor activity may synergize with venetoclax to increase response rates. One approach to enhance the potency of venetoclax is through combination with targeted radiotherapy. Studies have shown that DNA damage reduces the level of MCL1, a known mediator of venetoclax resistance, in tumor cells. The monoclonal antibody radioconjugate lintuzumab-Ac225 is a highly cytotoxic alpha-radiation emitter that selectively targets CD33, a cell surface antigen expressed on the majority of AML cells. The high-energy alpha-particle emissions from lintuzumab-Ac225 elicit single and double-strand DNA breaks in targeted tumor cells, and prior clinical studies have demonstrated single-agent anti-leukemic activity. In venetoclax-resistant cell lines in vitro, lintuzumab-Ac225 promotes MCL1 degradation through DNA damage, resulting in increased cell sensitivity to venetoclax. Similarly, mouse xenograft models with venetoclax-resistant AML tumor lines demonstrated tumor regression and increased survival in mice receiving both venetoclax and lintuzumab-Ac225. Objective Determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 when given in combination with venetoclax; Establish preliminary efficacy at MTD. Design Multicenter, open-label, dose-finding Phase I study followed by a Phase II trial. Setting Ongoing in the USA. Patients Patients aged >18 years with relapsed/refractory AML. Interventions Lintuzumab-Ac225 in combination with venetoclax. Main outcome measures Phase I: Assess dose-limiting toxicities (DLTs) to establish the MTD; Phase II: Determine the best overall response (CR+CRh) of the MTD 6 months after starting treatment. Results and Conclusions Ongoing study, no results available yet.