A Phase I Study of FT538, a First-of-Kind, Off-the-Shelf, Multiplexed Engineered, iPSC-Derived NK Cell Therapy As Monotherapy in Relapsed/Refractory Acute Myelogenous Leukemia and in Combination with Daratumumab or Elotuzumab in Relapsed/Refractory Multiple Myeloma
Authors: Janakiram Murali , Vij Ravi , Siegel David S. , Shih Ted , Weymer Sara , Valamehr Bahram , Chu Yu-Waye , Miller Jeffrey S. 
Published: November 2020

Background: Allogeneic natural killer (NK) cell therapies have been well-tolerated with documented anti-tumor activity in patients with relapsed/refractory (r/r) hematologic malignancies including acute myelogenous leukemia (AML) and multiple myeloma (MM) (Lupo et al. 2019). Allogeneic NK cell therapies may offer an improved safety profile characterized by the absence of cytokine release syndrome and neurologic toxicity compared with T-cell therapies (Liu et al. 2020). However, in comparison to T cells, NK cells have limited in vivo expansion and a short half-life, and the potential to generate deeper and more durable anti-tumor responses through multi-dose administration is limited by the inability to consistently manufacture and administer more than one dose of allogeneic NK cells.
The monoclonal antibodies (mAbs) daratumumab and elotuzumab have demonstrated clinical benefit and are approved for the treatment of MM (Darzalex® USPI, Empliciti® USPI). However, durable responses and disease-free survival remain limited. Engagement of the Fc portion of the mAb with CD16 on NK cells, which promotes antibody-dependent cellular cytotoxicity (ADCC), is a major contributor to the efficacy of daratumumab and elotuzumab. It is hypothesized that more clinically meaningful outcomes may be achieved by combining therapeutic mAbs with allogeneic NK cells engineered to enhance ADCC.
FT538 is an investigational, first-of-kind, multiplexed engineered NK cell therapy generated from a clonal master engineered induced pluripotent stem cell (iPSC) line, which can be used as a renewable source for the mass production of off-the-shelf NK cells for broad patient access. FT538 is engineered with three modalities for enhanced innate immunity: (1) high-affinity 158V, non-cleavable CD16 Fc receptor for augmented ADCC; (2) interleukin (IL)-15/IL-15 receptor fusion that promotes cytokine-autonomous persistence; and (3) CD38 knockout to mitigate NK cell fratricide by CD38-directed mAbs. In preclinical studies, FT538 combined with daratumumab against MM targets demonstrated avoidance of daratumumab-mediated fratricide and significantly enhanced ADCC in vitro in a serial stimulation cytotoxicity assay compared with peripheral blood NK cells, and the combination of FT538 with daratumumab led to highly effective tumor control compared with daratumumab alone in an in vivo MM xenograft model (Bjordahl et al. 2019).
Study Design and Methods: This study is a multicenter, multi-dose, Phase I clinical trial of FT538 in patients with r/r AML or r/r MM. The primary objectives are to determine the recommended Phase II dose of FT538 as monotherapy in r/r AML and in combination with daratumumab or elotuzumab in r/r MM. Key secondary objectives include evaluation of FT538 safety and tolerability, anti-tumor activity, and pharmacokinetics (PK) as monotherapy in r/r AML and combined with mAbs in r/r MM. Exploratory objectives include characterization of FT538 pharmacodynamics as assessed by peripheral blood biomarkers, assessment of minimal residual disease, and characterization of the tumor microenvironment in pre- and post-treatment tumor biopsies.
The dose-escalation part of the trial utilizes a 3+3 design to identify the maximum tolerated dose of up to three doses of FT538 on Days 1, 8, and 15 as a monotherapy in r/r AML (Regimen A) and in combination with daratumumab (Regimen B) or elotuzumab (Regimen C) in r/r MM. The dose-expansion part of the trial will further characterize the safety, efficacy, and PK of FT538 in all regimens. The trial will test up to five FT538 dose levels ranging from 50 million to 1.5 billion cells. Up to 105 patients will be enrolled. The mAbs in Regimens B and C will be administered based on dosing schedules per their respective prescribing information. Lympho-conditioning consisting of three consecutive days of fludarabine and cyclophosphamide will be administered prior to the first dose of FT538. Key inclusion criteria include r/r disease after standard approved therapies for r/r AML or r/r MM, as applicable, measurable disease for r/r MM, and adequate organ function. Key exclusion criteria include active central nervous system disease, need for systemic immunosuppressive therapy, and prior allograft organ transplant. This trial is expected to begin patient enrollment in 2020.

Disclosures
Janakiram: Takeda, Fate, Nektar: Research Funding. Siegel:Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Shih:Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Weymer:Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Valamehr:Fate Therapeutics, Inc: Current Employment, Current equity holder in publicly-traded company. Chu:Roche Holding AG: Current equity holder in publicly-traded company; Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Miller:Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Vycellix: Consultancy; Onkimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
Cyclophosphamide and fludarabine will be used as lympho-conditioning therapy prior to FT538 administration.