Lintuzumab-225Ac in Combination with Venetoclax in Relapsed/Refractory AML: Early Results of a Phase I/II Study

Background:

Overexpression of anti-apoptotic proteins such as MCL-1 has been implicated in resistance to the BCL2 inhibitor venetoclax in relapsed/refractory AML (R/R-AML). Therapeutic agents that reduce resistance to venetoclax as well as exhibiting intrinsic anti-tumor activity may synergize with venetoclax to increase response rates in this difficult to treat patient population. One approach to enhance the potency of venetoclax is through combination with targeted radiotherapy. Studies have shown that radiation-induced DNA damage reduces the level of MCL1 in tumor cells. The monoclonal antibody radioconjugate lintuzumab-²²⁵Ac is a highly cytotoxic alpha-radiation emitter that selectively targets CD33, a cell surface antigen expressed on the majority of AML cells but not on non-hematopoietic tissues. Prior clinical studies with lintuzumab-²²⁵Ac have demonstrated potent single agent anti-leukemic activity (ASH 2017, 2018). The short range, high-energy alpha-particle emissions from lintuzumab-²²⁵Ac elicit single and double-strand DNA breaks in targeted tumor cells. In venetoclax-resistant cell lines in vitro, lintuzumab-²²⁵Ac promotes MCL1 degradation resulting in increased cell sensitivity to venetoclax. In vivo mouse xenograft models with venetoclax-resistant AML tumor lines demonstrated enhanced tumor regression and increased survival in mice receiving both venetoclax and lintuzumab-²²⁵Ac. This study is the first study to combine radioimmunotherapy with venetoclax in patients with R/R-AML.

Study Design:

The Phase I portion of the study will use a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of lintuzumab-²²⁵Ac when given in combination with venetoclax. The planned dose levels for lintuzumab-²²⁵Ac are 0.5, 1.0, and 1.5 µCi/kg. As an exploratory endpoint, BH3 profiling will be performed on patient marrow samples to assess for MCL1 activity.

Eligible patients include R/R-AML patients aged 18 years and older with adequate organ function, ECOG Performance Status 0-2, and more than 25% of leukemic blasts CD33 positive by flow cytometry. Patients with antecedent MDS, MPNs, or therapy-related AML are eligible. Other than the cycle 1 dose ramp up to reduce the risk of tumor lysis syndrome, patients receive venetoclax at 400 mg/day PO on Days 1 to 21 of each cycle with dose modification for the use of CYP3A inhibitors. The Lintuzumab-²²⁵Ac is administered as a single dose on Day 1 of each cycle (see Study Schema).

Results:

Three R/R AML patients with a median age of 54 years (range 49-75) have been enrolled to date (see Table 1). The enrolled patients had a median of 2 therapies (2-3) and a median bone marrow blast percentage of 30% (range 20 - >60). All 3 patients had poor risk with adverse cytogenetics, and each patient has an additional high-risk marker (FLT3-ITD+, antecedent JAK2+ myelofibrosis, or TP53 mutation).

There have been no lintuzumab-²²⁵Ac related dose limiting toxicities (DLT) or non-hematologic Grade 3 or greater related AEs.

Patient 1 obtained a partial response with a decrease in BM leukemic blasts from >60% to 30-40% after cycle 1. Efficacy in the other 2 patients at this dose level is too early to evaluate.

Conclusion:

Combining lintuzumab Ac225 with venetoclax in patients with R/R-AML has an acceptable initial clinical safety profile at the level of 0.5 µCi/kg of lintuzumab-²²⁵Ac. Results in the first lintuzumab-²²⁵Ac dose cohort are encouraging, and the trial will continue to enroll to evaluate the hypothesis that there will be clinical synergy consistent with pre-clinical studies.