FT538 in Combination With Daratumumab in AML Acute Myeloid Leukemia

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.

• Daratumumab/rHuPH20 (Drug), also known as Darzalex: Daratumumab 1800 mg co-formulated with 30,000 units of hyaluronidase (rHuPH20) given subcutaneously into subcutaneous tissue of the abdomen approximately 3 inches \[7.5 cm\] to the right or left of the navel over approximately 3-5 minutes on Day -12 and Day -5 prior to the 1st FT538 infusion, and on Day +3, Day+10, and Day+17 approximately 48 hours after each FT538 infusion.
• FT538 (Drug): FT538 is administered as an IV infusion via gravity using an IV administration set with an in-line filter at the patient's assigned dose levels (DL) on Day 1, Day 8, and Day 15
• Fludarabine (Drug), also known as FLUDARA: Fludarabine 25 mg/m\^2 is administered as a 1 hour intravenous (IV) infusion per institutional guidelines once a day on 2 consecutive days (Day -4, and Day -3).
• Cyclophosphamide (Drug), also known as CYTOXAN, NEOSAR: Cyclophosphamide 300 mg/m\^2 is administered as a 2 hour intravenous (IV) infusion per institutional guidelines once a day on the same days that fludarabine is given.

Primary outcomes

• Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events [42 days from the 1st FT538 infusion]: Dose limiting toxicity (DLT) is defined as any AE (based on CTCAE v5) that is at least possibly related to FT538 that occurs after the first FT538 infusion through the end of the DLT assessment period on Day 29 as defined below: Any Grade 4 non-hematologic AE, Grade 3 pulmonary or cardiac AE of any duration, Grade 3 immune cell associated neurotoxicity syndrome (ICANS) of any duration, Any other Grade 3 non-hematologic AE of >72 hours duration or Grade ≥2 acute GvHD requiring systemic steroid administration

Secondary outcomes

• Number of Participants Achieving Complete Remission (CR + CRi) [28 days from the 1st FT538 infusion]: Efficacy of treatment is measured by the objective response rate (Complete Remission \[CR\] + Complete Remission with Incomplete Hematologic Recovery \[CRi\]) assessed by Day 28 based on the 2017 European LeukemiaNet (ELN) response criteria CR - defined as bone marrow blast <5%, absence of circulating blasts and blasts with auer rods, absence of extramedullary disease, Absolute neutrophil count >= 1.0 × 10e9/L (1000/μL) and platelet count >=100 × 10e9/L 100,000/μL) CRi - defined as all CR criterial except for residual neutropenia (<1.0 × 10e9/L \[1000/μL\]) or thrombocytopenia (<100 × 10e9/L \[100,000/μL\])
• Overall Response Rate [12 months from the 1st FT538 infusion]: Overall response rate is defined as number of patients who have a partial or complete response to therapy divided by the total number of patients who received treatment. Response criteria will be based on 2017 European LeukemiaNet (ELN) response criteria assessing the bone marrow blast percentage, presence/absence of circulating blasts, presence/absence of blasts with auer rods, presence/absence of extramedullary disease, Absolute neutrophil counts per liter pf blood and platelet counts per liter blood
• Percentage of Participants With Progression Free Survival (PFS) [12 months from the 1st FT538 infusion]: Percentage of participants experiencing progression free survival at one year follow up
• Percentage of Participants With Overall Survival (OS) [12 months from the 1st FT538 infusion]: Percentage of participants with Overall Survival (OS) at one year follow up
• Number of Participants Experiencing Adverse Events [12 months from the 1st FT538 infusion]: Number of participants experiencing adverse events with the combination of Daratumumab and FT538

Sex: All, ages: 12 Years to any

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.

Participant flow

Outcome results

• Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events (Primary), Number, Count of Participants: Dose Level 1: FT538 at 1 x10^8 Cells/Dose 0 (0 to 0.89); Dose Level 2: FT538 at 3 x10^8 Cells/Dose 0 (0 to 0.89); Dose Level 3: FT538 at 1 x10^9 Cells/Dose 0 (0 to 0.89); Dose Level 4: FT538 at 1.5 x10^9 Cells/Dose 0 (0 to 0.31)
• Number of Participants Achieving Complete Remission (CR + CRi) (Secondary), Number, Count of Participants: Dose Level 1: FT538 at 1 x10^8 Cells/Dose 0 (0 to 0.89); Dose Level 2: FT538 at 3 x10^8 Cells/Dose 0 (0 to 0.89); Dose Level 3: FT538 at 1 x10^9 Cells/Dose 0 (0 to 0.89); Dose Level 4: FT538 at 1.5 x10^9 Cells/Dose 2 (0.72 to 3.9)
• Overall Response Rate (Secondary), Number, participants: Dose Level 1: FT538 at 1 x10^8 Cells/Dose 0 (0 to 0.89); Dose Level 2: FT538 at 3 x10^8 Cells/Dose 0 (0 to 0.89); Dose Level 3: FT538 at 1 x10^9 Cells/Dose 0 (0 to 0.89); Dose Level 4: FT538 at 1.5 x10^9 Cells/Dose 2 (0.72 to 3.9)
• Percentage of Participants With Progression Free Survival (PFS) (Secondary), Number, Percentage of participants: Dose Level 1: FT538 at 1 x10^8 Cells/Dose 0 (0 to 0.89); Dose Level 2: FT538 at 3 x10^8 Cells/Dose 100 (0.10 to 100); Dose Level 3: FT538 at 1 x10^9 Cells/Dose 0 (0 to 0.89); Dose Level 4: FT538 at 1.5 x10^9 Cells/Dose 33 (12 to 65)
• Percentage of Participants With Overall Survival (OS) (Secondary), Number, Percentage of participants: Dose Level 1: FT538 at 1 x10^8 Cells/Dose 0 (0 to 0.89); Dose Level 2: FT538 at 3 x10^8 Cells/Dose 100 (0.10 to 100); Dose Level 3: FT538 at 1 x10^9 Cells/Dose 0 (0 to 0.89); Dose Level 4: FT538 at 1.5 x10^9 Cells/Dose 33 (12 to 65)
• Number of Participants Experiencing Adverse Events (Secondary), Number, Count of Participants: Dose Level 1: FT538 at 1 x10^8 Cells/Dose 1; Dose Level 2: FT538 at 3 x10^8 Cells/Dose 1; Dose Level 3: FT538 at 1 x10^9 Cells/Dose 1; Dose Level 4: FT538 at 1.5 x10^9 Cells/Dose 6

Adverse events

Time frame: 1 year

Serious adverse events by term

Other adverse events by term

17 more terms not shown.

• Study Protocol and Statistical Analysis Plan (PDF, 2023-05-08)
• Informed Consent Form (PDF, 2023-05-23)

• Joseph Maakaron, MD, Principal investigator, Masonic Cancer Center, University of Minnesota