FT538 in Combination With Daratumumab in AML Acute Myeloi... | NCT04714372

ID	Type	Description	Link
MT2020-33	Other Identifier	University of Minnesota Masonic Cancer Center

Description Module

Detailed Description

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Dose Level 1: FT538 at 1 x10^8 cells/dose	Experimental	FT538 administered at assigned dose as an IV infusion via gravity on Day 1, Day 8, and Day 15	Drug: Daratumumab/rHuPH20 Drug: FT538 Drug: Fludarabine Drug: Cyclophosphamide
Dose Level 2: FT538 at 3 x10^8 cells/dose	Experimental	FT538 administered at assigned dose as an IV infusion via gravity on Day 1, Day 8, and Day 15	Drug: Daratumumab/rHuPH20 Drug: FT538 Drug: Fludarabine Drug: Cyclophosphamide
Dose Level 3: FT538 at 1 x10^9 cells/dose	Experimental	FT538 administered at assigned dose as an IV infusion via gravity on Day 1, Day 8, and Day 15	Drug: Daratumumab/rHuPH20 Drug: FT538 Drug: Fludarabine Drug: Cyclophosphamide
Dose Level 4: FT538 at 1.5 x10^9 cells/dose	Experimental	FT538 administered at assigned dose as an IV infusion via gravity on Day 1, Day 8, and Day 15	Drug: Daratumumab/rHuPH20 Drug: FT538 Drug: Fludarabine Drug: Cyclophosphamide

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Daratumumab/rHuPH20	Drug	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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events	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	42 days from the 1st FT538 infusion

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants Achieving Complete Remission (CR + CRi)	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])

Eligibility Module

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.

Name	Affiliation	Role
Joseph Maakaron, MD	Masonic Cancer Center, University of Minnesota	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Masonic Cancer Center, University of Minnesota		Minneapolis	Minnesota	55455	United States

Arm/Group Information

ID	Title	Description
FG000	Dose Level 1: FT538 at 1 x10^8 Cells/Dose	FT538 administered at assigned dose as an IV infusion via gravity on Day 1, Day 8, and Day 15 Daratumumab/rHuPH20: 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: 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: 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: 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.
FG001	Dose Level 2: FT538 at 3 x10^8 Cells/Dose	FT538 administered at assigned dose as an IV infusion via gravity on Day 1, Day 8, and Day 15 Daratumumab/rHuPH20: 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: 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: 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: 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.
FG002	Dose Level 3: FT538 at 1 x10^9 Cells/Dose	FT538 administered at assigned dose as an IV infusion via gravity on Day 1, Day 8, and Day 15 Daratumumab/rHuPH20: 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: 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: 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: 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.
FG003	Dose Level 4: FT538 at 1.5 x10^9 Cells/Dose	FT538 administered at assigned dose as an IV infusion via gravity on Day 1, Day 8, and Day 15 Daratumumab/rHuPH20: 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: 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: 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: 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.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Dose Level 1: FT538 at 1 x10^8 Cells/Dose	FT538 administered at assigned dose as an IV infusion via gravity on Day 1, Day 8, and Day 15 Daratumumab/rHuPH20: 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: 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: 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: 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.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events

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

Posted

Number

90% Confidence Interval

Count of Participants

42 days from the 1st FT538 infusion

ID	Title	Description
OG000	Dose Level 1: FT538 at 1 x10^8 Cells/Dose	FT538 administered at assigned dose as an IV infusion via gravity on Day 1, Day 8, and Day 15 Daratumumab/rHuPH20: 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: 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: 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: 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.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Dose Level 1: FT538 at 1 x10^8 Cells/Dose	FT538 administered at assigned dose as an IV infusion via gravity on Day 1, Day 8, and Day 15 Daratumumab/rHuPH20: 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: 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: 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: 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.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Other, specify - Disease progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)		Systematic Assessment

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	May 8, 2023	Jun 17, 2024	Prot_SAP_000.pdf
ICF	No	No	Yes	Informed Consent Form	May 23, 2023	Jun 17, 2024	ICF_001.pdf

ID	Term
D015470	Leukemia, Myeloid, Acute
D007951	Leukemia, Myeloid
D007948	Leukemia, Monocytic, Acute

ID	Term
D007938	Leukemia
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D006402	Hematologic Diseases

ID	Term
D010752	Phosphoramide Mustards
D009588	Nitrogen Mustard Compounds
D009150	Mustard Compounds
D006846	Hydrocarbons, Halogenated

ID	Term
C556306	daratumumab
C024352	fludarabine
C042382	fludarabine phosphate
D003520	Cyclophosphamide