FT538 in Combination With Daratumumab in AML Acute Myeloid Leukemia

This Phase I open-label dose escalation study is conducted in two stages with a primary endpoint to identify the maximum tolerated dose (MTD) of FT538 when administered with daratumumab in patients 12 years and older with advanced acute myeloid leukemia (AML) and related myeloid diseases.

FT538 is an off the shelf product comprised of allogeneic natural killer (NK)-cell immunotherapy lacking CD38 and expressing hnCD16 and IL-15RF. Daratumumab is a targeted therapy (IgG1k human monoclonal antibody) that targets CD38.

FT538 is administered once a week for 3 consecutive weeks (Day 1, Day 8, and Day 15). Up to 5 dose levels will be tested. Fixed dose subcutaneous daratumumab is given on Day -12 and Day 5 prior to the NK cells as lymphodepletion, and on Day +3, Day +10, and Day +17 to maximize targeting. A short course of outpatient lymphodepleting chemotherapy is given on Day -4 and Day -3 to promote adoptive transfer. Day 1, the day of the 1st FT538 infusion, must be a Monday.

The primary analysis for Phase I is intent-to-treat in that all patients receiving the 1st infusion of FT538 are evaluable for toxicity and efficacy. Patients who discontinue therapy prior to the first FT538 will be replaced.

There are five potential FT538 dose cohorts. The starting dose is FT538 1x10e8 cells per dose with a lower safety dose of 5x10e7 if needed (Dose Level -1). The subsequent planned FT538 cohorts are 3x10e8, 1x10e9, and 1.5 x10e9 FT538 cells per dose. Dosing is based on hnCD16 expression, where 90% ± 10% of administered FT538 cells express hnCD16. The trial is conducted with no intra-patient escalation.

Eligibility Criteria:
Disease specific Inclusion Criteria:

Acute myeloid leukemia relapsed/refractory after 2 lines of therapy; with CD38 expression

* CD38 expression is defined by ≥20% of malignant cells with CD38 expression by flow cytometry on the most recent marrow biopsy (within 30 days of enrollment - archived or fresh).
* Relapsed/refractory is defined as failure to achieve at least a Morphological Leukemia Free State (MLFS) or reverting from MLFS.
* Lines of therapy are defined as (must have had 2 prior therapies):

  * One cycle of Intensive induction chemotherapy such as 7+3, 5+2, MEC, FLAG, FLAG-Ida, CLAG ± small molecule inhibitor
  * Four weeks of HMA-based induction ± small molecule inhibitor
  * Hematopoietic stem cell transplantation (HSCT) if relapse that occurs \> 90 days after HSCT
  * Gemtuzumab Ozogamicin
  * LDAC + glasdegib
  * Biomarker-specific targeted agents (FLT3 inhibitors, IDH1/2 inhibitors, others if available)
  * Other treatments could be considered after discussion with the PI

Inclusion Criteria:

* Age 12 years or older at the time of consent - Please note, enrollment of minors will be begin until permission to proceed is received from the FDA. At that time, the protocol will be updated to open enrollment to minors.
* Weight ≥ 50 kg due to FT538 fixed cell dosing and FT538 product pre-dose packaging
* Karnofsky performance status of 80-100% for 16 years and older or Lansky Play Score of 80-100 for ≥12 and \< 16 years of age
* Evidence of adequate organ function within 14 days of starting study treatment defined as:

  * Estimated Glomerular Filtration Rate (estimated creatinine clearance) ≥50 mL/min/1.73m\^2
  * Total bilirubin ≤ 5 × upper limit normal (ULN), not applicable for patients with Gilbert's syndrome
  * AST ≤3 × ULN and ALT ≤ 3 × ULN, not applicable if determined to be directly due to underlying malignancy
  * LVEF ≥ 40% by echocardiogram or MUGA
* Contraceptive use by men or women

  * Female subjects: Women of childbearing potential (WOCBP) must use a highly effective form of contraception from the screening visit until at least 12 months after the final dose of cyclophosphamide (CY), at least 4 months after the final dose of FT538, and at least 3 months after the final dose of daratumumab, whichever is latest.
  * Male subjects: Males with a female partner of childbearing potential or a pregnant female partner must be sterile (biologically or surgically) or use a highly effective method of contraception from the screening visit until at least 4 months after the final dose of CY and at least 4 months after the final dose of FT538, and at least 3 months after the final dose of daratumumab, whichever is latest.
* Must agree to and sign the consent for the companion Long-Term Follow-Up study (UMN CPRC #2020LS166) to fulfill the FDA required 15 years of follow-up for a genetically modified cell product.
* Must agree to and sign the consent for the companion Long-Term Follow-Up study (UMN CPRC #2020LS166) to fulfill the FDA required 15 years of follow-up for a genetically modified cell product.

Exclusion Criteria:

* Diagnosis of acute promyelocytic leukemia (APL)
* Pregnant or breastfeeding, Menstruating females of child-bearing potential must have a negative pregnancy test within 14 days of study treatment start
* Known allergy to any of study drugs or their components
* Clinically significant cardiovascular disease including any of the following: myocardial infarction within 6 months prior to first study treatment; unstable angina or congestive heart failure of New York Heart Association Grade 2 or higher or cardiac ejection fraction \<40%
* Any known condition that requires systemic immunosuppressive therapy (\> 5mg prednisone daily or equivalent) during the FT538 dosing period (3 days before the 1st dose through 14 days after the last dose) excluding pre-medications - inhaled and topical steroids are permitted
* Receipt of any biological therapy, chemotherapy, or radiation therapy, except for palliative purposes, within 2 weeks prior to Day 1 or five half-lives, whichever is shorter; or any investigational therapy within 28 days prior to the to the first dose of daratumumab. Maintenance hydroxyurea for blast control up to the initiation of lympho-conditioning is permitted
* Known active central nervous system (CNS) involvement or treated CNS disease that has not cleared. If prior disease related CNS involvement must have completed effective treatment of their CNS disease at least 2 months prior to Day 1 with no evidence of disease clinically and at least stable findings on relevant CNS imaging
* Non-malignant CNS disease such as epilepsy, CNS vasculitis, or neurodegenerative disease or receipt of medications for these conditions in the 2-year period leading up to study enrollment
* Clinically significant untreated/uncontrolled infection
* Live vaccine \<6 weeks prior to start of lympho-conditioning
* Known seropositive for HIV or known active Hepatitis B or C infection with detectable viral load by PCR
* Prior solid organ transplant
* Allogeneic HSCT relapse occurring \<90 days after HSCT
* Active graft-versus-host-disease (GvHD) requiring systemic immunosuppression within 14 days prior to enrollment
* Presence of any medical or social issues that are likely to interfere with study conduct or may cause increased risk to the participant.