Early Clinical Evaluation of Potential Synergy of Targeted Radiotherapy with Lintuzumab-Ac225 and Venetoclax in Relapsed/Refractory AML

Background: Resistance to venetoclax, a BCL2 inhibitor, has been shown to be mediated by co-expression of other BCL2 proteins including BCLXL and MCL1 in relapsed/refractory AML (R/R AML). Therapeutic agents reducing resistance to BCL2 inhibitors and exhibiting anti-tumor activity could synergize with venetoclax to increase response rates further. One approach to enhance the potency of venetoclax is through combination with targeted radiotherapy. Studies in tumor cells have shown 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 majority of AML cells. The high-energy alpha-particle emissions from lintuzumab-Ac225 as a single agent elicits single and double-strand DNA breaks in targeted tumor cells as demonstrated from prior clinical studies. (ASH 2017, 2018). 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. 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 uses a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of lintuzumab-Ac225 when given in combination with venetoclax. The dose levels for lintuzumab-Ac225 are 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 will enroll up to an additional 20 patients and treat with 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 include R/R-AML patients aged 18 years and older with adequate organ function, ECOG Performance Status 0-2, and more than 25% CD33 positive of leukemic blasts by flow cytometry. Patients with antecedent MDS, MPNs, or therapy-related AML are eligible. During Cycle 1, venetoclax dosing is ramped up during the first 4 days in order to minimize the risk of tumor lysis syndrome (TLS). After Cycle 1, all patients may receive up to four cycles of venetoclax at 400 mg/day PO on Days 1 to 21 of each cycle. Lintuzumab-Ac225 is administered as a single dose of each cycle.

Results: Fifteen R/R AML patients were treated with lintuzumab-Ac225 at 0.5 µCi/kg (n=3), 0.75 µCi/kg (n=6), 1.0 µCi/kg (n=3), and 1.5 µCi/kg (n=3) in combination with venetoclax in the phase I dose escalation portion as of 1-August-2022. The median age was 71 years (range 46-87) with 7/15 (47%) refractory; 9/15 (60%) had unfavorable risk (ELN). The study patients enrolled in the first cohort at dose level 0.5 µCi/kg of lintuzumab-Ac225 in combination with venetoclax demonstrated a clinically acceptable safety profile, and no DLTs were observed. An intermediate Cohort 2B at dose level 0.75 µCi/kg, was implemented. One of 6 patients experienced one DLT with Grade 3 prolonged thrombocytopenia in cohort 2B. No DLTs were observed at 1.0 µCi/kg (Cohort 2) and 1.5 µCi/kg (Cohort 3) of lintuzumab-Ac225 in combination with 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). There were no early deaths (≤30d) in any cohort. During the dose escalation phase, the responses (CR/CRi) have been observed in 2 patients with TP53 mutation. The acceptable safety profile of lintuzumab-Ac225 up to 1.5 µCi/kg in combination with venetoclax in R/R AML has been demonstrated. Based on the SRC's recommendation, expansion cohorts have been implemented to determine the MTD, efficacious dose and dosing schedule of lintuzumab-Ac225 in combination with venetoclax in patients with R/R AML.

Conclusion: Combining lintuzumab-Ac225 up to 1.5 µCi/kg with venetoclax in patients with R/R AML has an acceptable clinical safety profile with no mortality at day 30. The MTD, efficacious dose and dosing schedule of lintuzumab-Ac225 in combination with venetoclax is currently investigated in ongoing Phase I Cohort Expansion.

Schiller:Arog: Research Funding; PreCOG LLC: Research Funding; FujiFilm: Research Funding; AVM Biopharma: Research Funding; Incyte: Other: speaker fees, Research Funding, Speakers Bureau; Mateon: Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria, Other: Speaker fees, Research Funding; Pfizer: Research Funding; Gilead: Research Funding; Jazz: Consultancy; Daiichi-Sankyo: Research Funding; Janssen: Research Funding; Sellas: Research Funding; Gamida: Research Funding; Medimmune: Research Funding; Onconova: Research Funding; Actuate: Research Funding; Glycomimetics: Research Funding; Forma: Research Funding; Deciphera: Research Funding; Deltafly: Research Funding; Genentech-Roche: Research Funding; Stemline: Research Funding; Samus: Research Funding; Cellectis: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Regimmune: Research Funding; Geron: Research Funding; Stemline: Speakers Bureau; Kite, a Gilead Company: Research Funding, Speakers Bureau; Constellation: Research Funding; Trovagen: Research Funding; AltruBio: Research Funding; CTI: Research Funding; AbbVie: Research Funding, Speakers Bureau; Bristol Myers Squibb: Current equity holder in publicly-traded company, Speakers Bureau; Cellerant: Research Funding; Amgen: Current equity holder in publicly-traded company, Honoraria; Celgene: Consultancy, Research Funding, Speakers Bureau; Ono Pharma: Honoraria; Actinium: Research Funding; Cyclacel: Research Funding; Astellas: Research Funding, Speakers Bureau; Sangamo: Research Funding; Millennium: Research Funding; Karyopharm: Research Funding, Speakers Bureau; Agios: Consultancy, Honoraria; Takeda: Research Funding; Tolero: Research Funding. Orozco:Actinium Pharmaceuticals, Inc.: Other: Site PI for clinical trial(s) sponsored by Actinium and Research Funding. Desai:Actinium Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Chen:Actinium Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Roboz:Jasper Therapeutics: Consultancy; Takeda: Consultancy; Onconova Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Other: Travel and Accommodation expenses, Research Funding; Bristol Myers Squibb: Consultancy; Roche: Consultancy; Array BioPharma: Other: Travel and accommodation expenses; Amphivena Therapeutics: Other: Travel and accommodation expenses, Research Funding; Clovis Oncology: Other: Travel and accommodation expenses; Astellas: Consultancy; Pfizer: Consultancy, Honoraria, Other: Travel and accommodation expenses; Jazz: Consultancy, Other: travel; Bristol Myers Squibb: Consultancy; Otsuka: Consultancy; Sandoz: Consultancy, Other: Travel and accommodation expenses; Daiichi Sankyo: Consultancy; MEI Pharma: Consultancy, Research Funding; Eisai: Other: Travel and accommodation expenses; Sunesis Pharmaceuticals: Other: Travel and accommodation expenses, Research Funding; Amgen: Consultancy, Other: travel; Mesoblast: Consultancy; Agios: Other: travel, Research Funding; Helsinn Therapeutics: Consultancy; Janssen: Consultancy, Other: travel and accommodation expenses, Research Funding; GlaxoSmithKline: Consultancy; Bayer: Consultancy, Other: Travel and accommodation expenses; Celgene: Consultancy, Other: travel and accommodation expenses, Research Funding; Genentech/Roche: Consultancy, Other: Travel and accommodation expenses; Celltrion: Consultancy, Other: Travel and accommodation expenses; MedImmune: Consultancy, Research Funding; Mofitt Cancer Center: Research Funding; Karyopharm Therapeutics: Research Funding; CTI: Research Funding; Novartis: Consultancy, Other: Travel and accommodation expenses, Research Funding; Amgen: Consultancy; Agios: Consultancy, Research Funding; AbbVie: Consultancy, Other: travel and accommodations, Research Funding; Tensha Therapeutics: Research Funding; Actinium: Consultancy.