Try the modernized ClinicalTrials.gov beta website. Learn more about the modernization effort.
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

FT538 in Combination With Daratumumab in AML Acute Myeloid Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04714372
Recruitment Status : Recruiting
First Posted : January 19, 2021
Last Update Posted : November 9, 2021
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Myeloid Leukemia Monocytic Leukemia Drug: Daratumumab/rHuPH20 Drug: FT538 Drug: Fludarabine Drug: Cyclophosphamide Phase 1

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: This study is performed in two stages, with Stage 1 having two potential steps. A minimum of 28 days separates each patient cohort. Stage 1 step 1 uses a fast-track design (1 patient per cohort) starting at Dose Level 1. The study moves to Stage 1 Step 2 when a pre-defined adverse event occurs during fast-track enrollment, specifically, any Grade 3 non-hematologic event within 72 hours after an FT538 infusion. The cohort size increases from 1 to 3 patients with 2 additional patients added to the current cohort if the event being a Dose Limiting Toxicity (DLT) event. No intra-cohort staggering is required. Escalation in Step 2 continues until the 1st DLT event at which point Stage 2 (CRM) is activated. Stage 2 follows Continual Reassessment Method (CRM) and is initiated at the 1st DLT
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study of FT538 in Combination With Daratumumab in Acute Myeloid Leukemia
Actual Study Start Date : November 3, 2021
Estimated Primary Completion Date : December 15, 2025
Estimated Study Completion Date : December 15, 2025


Arm Intervention/treatment
Experimental: 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
Drug: 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.
Other Name: Darzalex

Drug: 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

Drug: 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)
Other Name: FLUDARA

Drug: 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
Other Names:
  • CYTOXAN
  • NEOSAR

Experimental: 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
Drug: 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.
Other Name: Darzalex

Drug: 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

Drug: 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)
Other Name: FLUDARA

Drug: 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
Other Names:
  • CYTOXAN
  • NEOSAR

Experimental: 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
Drug: 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.
Other Name: Darzalex

Drug: 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

Drug: 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)
Other Name: FLUDARA

Drug: 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
Other Names:
  • CYTOXAN
  • NEOSAR

Experimental: 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
Drug: 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.
Other Name: Darzalex

Drug: 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

Drug: 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)
Other Name: FLUDARA

Drug: 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
Other Names:
  • CYTOXAN
  • NEOSAR




Primary Outcome Measures :
  1. Number of participants experiencing Dose Limiting Toxicity (DLT) events [ Time Frame: 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 Outcome Measures :
  1. Number of participants achieving complete remission (CR + CRi) [ Time Frame: 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])

  2. Overall Response Rate [ Time Frame: 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


  3. Number of participants with Progression Free Survival (PFS) [ Time Frame: 12 months from the 1st FT538 infusion ]
    Number of participants experiencing progression free survival at one year follow up

  4. Number of participants with Overall Survival (OS) [ Time Frame: 12 months from the 1st FT538 infusion ]
    Number of participants experiencing progression free survival at one year follow up

  5. Number of participants experiencing adverse events [ Time Frame: 12 months from the 1st FT538 infusion ]
    Number of participants experiencing adverse events with the combination of Daratumumab and FT538



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04714372


Contacts
Layout table for location contacts
Contact: Cancer Center Clinical Trials Office 612 624 2620 ccinfo@umn.edu

Locations
Layout table for location information
United States, Minnesota
Masonic Cancer Center, University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Joseph Maakaron, MD       maaka001@umn.edu   
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
Layout table for investigator information
Principal Investigator: Joseph Maakaron, MD Masonic Cancer Center, University of Minnesota
Layout table for additonal information
Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT04714372    
Other Study ID Numbers: 2020LS114
MT2020-33 ( Other Identifier: University of Minnesota Masonic Cancer Center )
First Posted: January 19, 2021    Key Record Dates
Last Update Posted: November 9, 2021
Last Verified: November 2021

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Masonic Cancer Center, University of Minnesota:
FT538, AML, Daratumumab, CD38
Additional relevant MeSH terms:
Layout table for MeSH terms
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cyclophosphamide
Fludarabine
Daratumumab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists