-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

4842 Phase I Study of FT538 + Daratumumab for Treatment of r/r AML

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster III
Hematology Disease Topics & Pathways:
Biological therapies, Acute Myeloid Malignancies, AML, Diseases, Therapies, Myeloid Malignancies, Natural Killer (NK) Cell Therapies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Joseph E. Maakaron, MD1, Cassie Seichter1*, Rose Wangen2*, Andrea Hoeschen1*, Deepa Kolaseri Krishnadas2*, Kateryna Kent1*, Ryan Shanley3*, Daniel O'Leary, MD4, Najla El Jurdi, MD5, Shernan G. Holtan, MD6, Brian Betts, MD4, Mark Juckett, MD4 and Jeffrey S Miller, MD7

1Masonic Cancer Center, University of Minnesota, Minneapolis, MN
2University of Minnesota, Minneapolis, MN
3Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
4Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN
5Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, minneapolis, MN
6Department of Medicine, Umn Medical School, Minneapolis, MN
7Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN

Introduction: Relapsed and refractory (r/r) acute myeloid leukemia (AML) remains an unmet need with immune-therapy based treatments such as hematopoietic stem cell transplantation (HSCT) providing the longest relapse-free survival (RFS). Natural Killer (NK cells) have been shown to effect lysis of AML cells, both in vitro and in vivo across multiple platforms. In particular, “adaptive” NK cells induced in vivo in HSCT recipients after CMV reactivation have been shown to confer an RFS advantage. These cells are characterized phenotypically by the expression of NKG2C, CD57, KIR and downregulation of CD38. CD38 is an ectoenzyme broadly expressed on hematopoietic cells, including approximately 60% of AML. It catalyzes the conversion of nicotinamide-adenine dinucleotide (NAD+) and nicotinamide-adenine dinucleotide phosphate (NADP+) to cyclic adenosine diphosphate (cADP) ribosyl. CD38 knock-out NK cells have increased persistence by having enhanced metabolic fitness and resistance to oxidative stress via a reduction of reactive oxygen species. FT538 is an iPSC-derived NK cell product with a non-cleavable CD16 receptor to augment antibody-dependent cytotoxicity (ADCC), IL-15/IL-15R fusion to increase activation and persistence, and CD38 knockout to enhance its metabolic fitness and avoid fratricide when combined with CD38 monoclonal antibodies. Daratumumab (Dara) is a monoclonal antibody targeting CD38 on the surface of AML cells as well as activated lymphocytes. We hypothesized that the addition of Dara to fludarabine and cyclophosphamide would enhance lymphodepletion and augment ADCC for CD38+ AML leading to better response rates when combined with FT538.

Methods: This (NCT04714372) is a phase I, dose-escalation study, utilizing FT538 in combination with fludarabine, cyclophosphamide, and Dara for the treatment of r/r AML. A study schema is presented in Figure 1A. Patients received 5 weekly doses of Dara starting day -12, 2 doses of fludarabine and cyclophosphamide at day -4, and 3 weekly doses of FT538. They were followed for DLT for 28 days after FT538 infusion. Patients with r/r AML after 2 or more lines of therapy and good organ function were enrolled. The primary objective was the safety of this combination, and the endpoints were the incidence of dose-limiting toxicities (DLTs) and incidence of adverse events. Secondary endpoint was the efficacy and predictors of efficacy. Patients evaluable for safety are those who received at least one dose of FT538. Patients evaluable for efficacy are those who completed all doses. Fast-track enrollment was utilized where one patient per dosing level (DL) was enrolled as long as no DLTs were seen with cohort expansion in the event of DLTs or related severe adverse events.

Results: Six patients were enrolled on 4 DLs with increasing dose of FT538 from 1x108 – 1.5x109 cells. Median age was 70 years. Median number of prior lines is 3.5 (3-4). All patients were refractory to most recent therapy. One patient was enrolled on each DL1, DL2, and DL3. Three enrolled on DL4 with 1 completing therapy. Five patients are evaluable for safety and 4 for efficacy. There were no DLTs and we were able to enroll one patient per cohort. Eighty percent (4/5) experienced febrile neutropenia and infections. One patient with a prior biliary stent had choledocholithiasis requiring a complicated intervention. No prolonged cytopenias attributable to FT538 were seen. One patient experienced a G1 CRS lasting 1 day. There were no neurotoxicity events.

One patient on DL2 achieved stable disease and one patient on DL4 achieved a CR for an ORR of 50% (2/4). Both went on to receive HSCT and continue to be alive and well without disease with a median follow up of 5 months. This is summarized in Figure 1.B. Macrochimerism (donor cells) was detected for up to 8 days post-infusion. Macrochimerism did not correlate with response but did show that Ki67 expression was present on donor cells suggesting proliferation.

Conclusions: FT538 in combination with daratumumab has been tolerated in a highly pre-treated cohort of patients with expected toxicities and a signal of efficacy.

Disclosures: Maakaron: FATE Therapeutics: Research Funding; Gilead: Research Funding; Atara: Research Funding; CLBR: Research Funding; CRISPR: Research Funding; Precision Biosciences: Research Funding. Holtan: CSL Behring: Other: Endpoint Adjudication Committee; Sanofi: Research Funding; Ossium: Consultancy; Incyte: Research Funding; Vitrac: Research Funding. Betts: CRISPR: Patents & Royalties; CTI Biopharma: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Vitrac Therapeutics: Research Funding. Miller: GT BioPharma: Consultancy, Current holder of stock options in a privately-held company, Patents & Royalties, Research Funding; Vycellix: Consultancy, Current holder of stock options in a privately-held company; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Patents & Royalties, Research Funding.

OffLabel Disclosure: Daratumumab - increasing lymphodepletion and targeting CD38+ AML

*signifies non-member of ASH