Updated Results from Phase 1 Study of Targeted Radiotherapy with Lintuzumab-Ac225 in Combination with Venetoclax in Relapsed/Refractory AML

Background:

Resistance to venetoclax, a BCL2 inhibitor, is mediated by co-expression of other BCL2 proteins including BCLXL and MCL1. In vitro data show that DNA damage reduces the level of MCL1, a known mediator of venetoclax resistance. 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. Clinical studies have shown that the high-energy alpha-particle emissions from lintuzumab-Ac225 elicit single and double-stranded DNA breaks in targeted tumor cells. In venetoclax-resistant cell lines in vitro, lintuzumab-Ac225 promotes MCL1 degradation through DNA damage resulting in increased cell sensitivity to venetoclax. Similarly, mice xenografted with venetoclax-resistant AML tumor lines demonstrated tumor regression and increased survival when treated with venetoclax and lintuzumab-Ac225. The aims of this phase I/II study are to assess the safety, tolerability and efficacy of lintuzumab-Ac225 in combination with venetoclax in R/R AML.

Study Design:

The Phase I portion of the study used a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 combined with venetoclax. The dose levels for lintuzumab-Ac225 were 0.5, 0.75, 1.0 µCi/kg, 1.5 µCi/kg, and 2.0 µCi/kg (expansion cohort). The Phase II portion of the study was designed to enroll up to an additional 20 patients at the recommended phase II dose (RP2D) with venetoclax to determine the best overall response (CR+CRh+CRi) up to 6 months after starting treatment.

Eligible patients included R/R AML patients aged 18 years and older with adequate organ function, ECOG performance status 0-2, and more than 25% CD33 positive leukemic blasts by flow cytometry. Patients with antecedent myelodysplastic syndromes, myeloproliferative neoplasms, or therapy-related AML were eligible. Venetoclax was given at a dose of 400 mg daily on days 1 to 21 (cohorts 1-3) or days 2-22 (cohort 4). Lintuzumab-Ac225 was administered as a single dose of each cycle on day 5 (cohorts 1-3) or day 1 (cohort 4).

Results:

In total, eighteen R/R AML patients received lintuzumab-Ac225 at 0.5 µCi/kg (n=3), 0.75 µCi/kg (n=6), 1.0 µCi/kg (n=3), 1.5 µCi/kg (n=3) and 2.0 µCi/kg (n=3) with venetoclax in the phase I dose escalation portion. The median age was 73 years (range 46-87); 7/18 (39%) had refractory AML and 9/18 (50%) had ELN unfavorable risk. In the dose escalation phase, one DLT with grade 3 prolonged thrombocytopenia occurred in 1 of 6 patients received lintuzumab-Ac225 at 0.75 µCi/kg plus venetoclax. No DLTs were observed at 1.0 µCi/kg (Cohort 2), 1.5 µCi/kg (Cohort 3) and 2.0 µCi/kg (Cohort 4) of lintuzumab-Ac225 plus venetoclax. Grade 3 or higher adverse events related to lintuzumab-Ac225 treatment included hematologic AEs and one count of non-hematologic event (hyponatremia) (Table 1). In cohort 4 at 2.0 µCi/kg of lintuzumab-Ac225 with the dosing schedule modification, reduction of BM blasts was observed in 2 of 3 patients. One patient achieved MLFS with 93% reduction of BM blasts.

Conclusion:

The combination of lintuzumab-Ac225 and venetoclax had a manageable safety profile and no early mortality at day 30. The MTD was not reached and no significant toxicities have been reported during the follow-up period. Modified dosing schedule in Cohort 4 of the combination demonstrated improved anti-leukemic effects. The data observed supports the development of further trials to evaluate the safety and anti-leukemic efficacy of lintuzumab-Ac225 in combination with venetoclax-based treatment in the R/R AML population.