Lintuzumab-Ac225 with Combination with Intensive Chemotherapy Yields High Response Rate and MRD Negativity in R/R AML with Adverse Features

Background: Actimab-A (lintuzumab-Ac225) is a humanized CD33 antibody conjugated to an alpha emitting isotope, Ac225, delivering high energy radiation over a short radius to CD33 expressing AML blasts and requiring no isolation. Preclinical studies also indicate that Actimab-A effectively depletes the anti-apoptotic protein MCL-1, potentially indicating another mechanism of action, which may benefit venetoclax resistant patients (pts). In this study, we hypothesized that low dose Actimab-A after salvage chemotherapy is feasible and improves clearance of residual, resistant AML thereby improving remission rates, and depth of remission. Herein, we report results of our Phase I study, and results of pts enrolled in an expansion cohort to characterize PK.

Methods: This study enrolled R/R AML pts deemed fit, with adequate organ function, and with CD33 expression on >25% of leukemic blasts. The primary endpoint of the Phase I study was determination of MTD of Actimab-A in combination with CLAG-M. Secondary endpoints included the composite complete remission (CRc) rate after one induction cycle, the MRD (-) CRc rate determined by multiparametric flow cytometry, median overall survival (OS), and estimated 1- and 2-year OS. Furthermore, we are performing an expansion cohort to characterize PK.

Induction consisted of G-CSF, 300mcg/d, given D1-6, cladribine 5mg/m2, given D2-6, cytarabine 2g/m2, given D2-6, and mitoxantrone 10mg/m2, given D2-4. Actimab-A was administered as a single dose on day 8 ±1 day The trial enrolled to 4 cohorts, with Actimab-A at doses ranging from 0.25uCi/kg to 1.0uCi/kg. One induction cycle was administered in all pts.

Results: Of the 21 pts evaluable for response, median age was 63 yrs, 52% (n=11) had s-AML/t-AML, 67% (n=14) had adverse cytogenetics, and TP53 mutations were present in 52% (n=11) of pts. Median blast CD33 expression at baseline was 77% (range: 29-100%). Pts received a median 2 lines of therapy, including 57% (n=12) who received prior venetoclax. 57% (n=12) of pts enrolled after relapse post allogeneic HCT (alloHCT) (Table 1).

The MTD was determined to be 1.0 uCi/kg, and the RP2D was set at 0.75uCi/kg. Within the 1.0uCi/kg dosing cohort, 2 DLTs were observed in 5 pts; severe mucositis and delayed ANC recovery (>42 days). Among all pts, Grade 3/4 toxicities observed in >10% of pts included febrile neutropenia, infection, rash and hypokalemia.

Overall, 52% (n=11) achieved CRc, an additional 14% (n=3) achieved an MLFS, for an ORR (CRc+MLFS) of 67%. MRD negativity by flow was observed in 72% of pts achieving a CRc. At the RP2D, 67% (n=4) achieved CRc, and 75% of these pts achieved MRD negativity by flow. An additional 1 patient achieved MLFS for an ORR=83%. Actimab-A+CLAG-M was active in pts with TP53 mutations (ORR 73%) and in those who received prior venetoclax (ORR 55%) (Table 1).

Median OS among all pts was 1.0 year (95% CI, 0.2 to 1.8); 1-year OS was 53% and 2-year OS was 32% (Figure 1). After therapy, 75% (n=6) of pts successfully bridged to alloHCT. Among patients who underwent 1st alloHCT, median OS was 2.5 years (95%CI, 1.0-3.9).

PK studies measuring blood radioactivity were performed in 3 pts. Blood Ac225 radioactivity studies revealed median tmax of 0.6 hrs after infusion start. After achieving Cmax, mean half-life of radioactivity was 9.8 hrs. Ac225 radioactivity was below the limit of quantification (BLQ) by 48 hrs in all pts.

Conclusions: Actimab-A at 0.75uCi/kg, combined with CLAG-M is feasible and safe, and this combination demonstrates a high response rate and MRD negativity in a high-risk AML population. Pharmacokinetics at the RP2D indicate rapid drug clearance. Furthermore, responses appear durable, particularly among patients who are able to proceed to alloHCT. In conclusion, with no viable options for both R/R TP53 mutated AML and R/R AML previously treated with venetoclax, this regimen represents a potentially important option, and efforts are underway for a confirmatory study.