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

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.4842-4842
• Main Authors: Maakaron, Joseph E., Seichter, Cassie, Wangen, Rose, Hoeschen, Andrea, Kolaseri Krishnadas, Deepa, Kent, Kateryna, Shanley, Ryan, O'Leary, Daniel, El Jurdi, Najla H, Holtan, Shernan G., Betts, Brian, Juckett, Mark, Miller, Jeffrey S
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-189132

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. Pa