Early Clinical Evaluation of Potential Synergy of Targeted Radiotherapy with Lintuzumab-Ac225 and Venetoclax in Relapsed/Refractory AML
Authors: Schiller Gary J. , Finn Laura , Roboz Gail J. , Orozco Johnnie J. , Lin Tiffany , Chen Mary M , Hegazi Mohamed M. 
Published: November 2021

Abstract
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, and 1.0 µCi/kg. 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 will be ramped up during the first 4 days in order to minimize the risk of tumor lysis syndrome (TLS). After Cycle 1, all patients will receive venetoclax at 400 mg/day PO on Days 1 to 21 of each cycle. Lintuzumab-Ac225 is administered as a single dose on Day 5 of each cycle.
Results:
Ten R/R AML patients were treated with lintuzumab-Ac225 at 0.5 µCi/kg (n=3), 0.75 µCi/kg (n=6) and 1.0 µCi/kg (n=1) in combination with venetoclax in the phase I dose escalation portion as of 1-August-2021. The median age was 67 years (range 49-83) with 5/10 (50%) refractory; 8/10 (80%) had unfavorable risk (ELN). Three patients were enrolled on the first cohort at dose level 0.5 µCi/kg of lintuzumab-Ac225 and showed clinically acceptable safety profile with no DLTs. In addition, one patient achieved CRi at the end of cycle 1. Results from the first cohort were encouraging and acceptable for dose escalation. An intermediate Cohort 2B at dose level 0.75 µCi/kg, was implemented. To date, 6 patients were enrolled on cohort 2B, and based on the Safety Committee recommendation, dose level at 1.0 µCi/kg may be resumed.
In preliminary data on all patients, lintuzumab-Ac225 treatment-related grades 3/4 adverse events (AEs) include hematologic AEs and only one count of non-hematologic event (hyponatremia) (Table 1). There were no early deaths (≤30d) in any cohort. Overall, lintuzumab-Ac225 can be combined with venetoclax with a manageable toxicity profile. While sample size is limited, ORR (CR/CRi) for all R/R AML patients and TP53-mutant R/R patients were 20% (2/10) and 67% (2/3), respectively. Updated safety and response data will be presented at ASH2021.
Conclusion:
Combining lintuzumab-Ac225 with venetoclax in patients with R/R AML has an acceptable clinical safety profile with 0% 30-day mortality rate. 67% ORR is particularly encouraging in TP53-mutant R/R AML. These data support the further evaluation of lintuzumab-Ac225 in combination with venetoclax in patients with R/R AML, especially in TP53-mutant R/R patients.
Figure 1 Figure 1.

Disclosures
Schiller: FujiFilm: Research Funding; Forma: Research Funding; Arog: Research Funding; Gamida Cell Ltd.: Research Funding; Karyopharm: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Geron: Research Funding; Mateon: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; PrECOG: Research Funding; Regimmune: Research Funding; Delta-Fly: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Actuate: Research Funding; Samus: Research Funding; Constellation Pharmaceuticals: Research Funding; Deciphera: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Research Funding; Takeda: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Sangamo: Research Funding; Genentech-Roche: Research Funding; Celator: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Astellas: Honoraria, Research Funding, Speakers Bureau; Trovagene: Research Funding; Tolero: Research Funding; Daiichi-Sankyo: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Bio: Research Funding; Ono-UK: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Finn: Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Speakers Bureau. Roboz: Mesoblast: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Janssen: Consultancy; Actinium: Consultancy; Blueprint Medicines: Consultancy; Jasper Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy; Astex: Consultancy; Helsinn: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Agios: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Otsuka: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy. Orozco: Actinium Pharmaceuticals, Inc.: Other: site PI for clinical trial(s) sponsored by Actinium, Research Funding. Lin: Actinium Pharmaceuticals, Inc.: Current Employment. Chen: Actinium Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company.

OffLabel Disclosure:
Venetoclax use in relapsed-refractory AML