FT538 in Subjects With Advanced Hematologic Malignancies

Study Overview
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Brief Summary
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This is a Phase I dose-finding study of FT538 as monotherapy in acute myeloid leukemia (AML) and in combination with monoclonal antibodies in multiple myeloma (MM). The study will consist of a dose-escalation stage and an expansion stage where participants will be enrolled into indication-specific cohorts.

Official Title
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A Phase I, Open-Label, Multicenter Study of FT538 as Monotherapy in Relapsed/Refractory Acute Myelogenous Leukemia and in Combination With Monoclonal Antibodies in Relapsed/Refractory Multiple Myeloma

Conditions
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Acute Myeloid Leukemia, AML, Adult, Multiple Myeloma, Myeloma

Intervention / Treatment
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* Drug: FT538
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Daratumumab
* Drug: Elotuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of one of the following by treatment regimen: Regimen A (FT538 monotherapy in r/r AML) Primary refractory AML, or Relapsed AML, defined as not in CR after one or more re-induction attempts; if >60 years of age, prior re-induction therapy is not required Regimens B or C (FT538 + mAb in r/r MM) Regimen B only: MM that has relapsed or progressed after at least two lines of therapies, including a proteasome inhibitor and an immunomodulatory drug Regimen C only: MM that has relapsed or progressed after proteasome inhibitor therapy, and immunomodulatory therapy Regimen B and Regimen C: Measurable disease as defined in the protocol Capable of giving signed informed consent Agreement to comply with study procedures as described in the Schedule of Activities Agrees to contraceptive use as described in the protocol Exclusion Criteria: Females who are pregnant or breastfeeding ECOG Performance Status ≥ 2 Evidence of insufficient hematologic function as defined in the protocol Evidence of insufficient organ function defined as defined by the protocol Clinically significant cardiovascular disease as defined by the protocol Known active central nervous system (CNS) involvement by malignancy Non-malignant CNS disease such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease or receipt of medications for these conditions in the 2-year period leading up to study enrollment Currently receiving or likely to require systemic immunosuppressive therapy for any reason during the treatment period Clinically significant infections including HIV, HBV and HCV Live vaccine <6 weeks prior to start of lympho-conditioning Receipt of an allograft organ transplant Prior allogeneic HSCT or allogeneic CAR-T within 6 months of Day 1, or ongoing requirement for systemic graft-versus-host therapy Known allergy to albumin (human) or DMSO Presence of any medical or social issues that are likely to interfere with study conduct or may cause increased risk to subject Any medical condition or clinical laboratory abnormality that per investigator or Medical Monitor judgement precludes safe participation in and completion of the study, or which could affect compliance with protocol conduct or interpretation of results Exclusion Criteria Specific to Regimen A (r/r AML) Diagnosis of promyelocytic leukemia with t(15;17) translocation 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 Day 1 Exclusion Criteria Specific to Regimens B and C (r/r MM) Plasma cell leukemia defined as a plasma cell count >2000/mm3 Leptomeningeal involvement of MM 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 first dose of mAb Allergy or hypersensitivity to antibodies or antibody-related proteins

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FT538 Monotherapy<br>FT538 monotherapy in subjects with r/r AML | Drug: FT538<br>* Experimental Interventional Therapy, Allogeneic Cell Therapy NK Cell<br>Drug: Cyclophosphamide<br>* Lympho-conditioning Agent<br>Drug: Fludarabine<br>* Lympho-conditioning Agent<br>|
| Experimental: FT538 in Combination with Daratumumab<br>FT538 in combination with daratumumab in subjects with r/r MM | Drug: FT538<br>* Experimental Interventional Therapy, Allogeneic Cell Therapy NK Cell<br>Drug: Cyclophosphamide<br>* Lympho-conditioning Agent<br>Drug: Fludarabine<br>* Lympho-conditioning Agent<br>Drug: Daratumumab<br>* Monoclonal Antibody, CD38, Anti-CD38<br>* Other names: Darzalex;|
| Experimental: FT538 in Combination with Elotuzumab<br>FT538 in combination with elotuzumab in subjects with r/r MM | Drug: FT538<br>* Experimental Interventional Therapy, Allogeneic Cell Therapy NK Cell<br>Drug: Cyclophosphamide<br>* Lympho-conditioning Agent<br>Drug: Fludarabine<br>* Lympho-conditioning Agent<br>Drug: Elotuzumab<br>* Monoclonal Antibody<br>* Other names: Empliciti;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) within each dose level cohort |  | Cycle 1, Up to Day 29 | 
| Nature of dose-limiting toxicities within each dose level cohort |  | Cycle 1, Up to Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence, nature, and severity of adverse events (AEs) of FT538 as monotherapy in r/r AML and in combination with daratumumab or elotuzumab in r/r multiple myeloma |  | Up to 5 years | 
| Objective response rate (ORR) of FT538 as monotherapy in r/r AML and in combination with daratumumab or elotuzumab in r/r MM | Proportion of subjects who achieve a CR, CRMRD-, CRi, MLFS, or PR, as determined by the investigator according to 2017 ELN criteria for AML, and the proportion of subjects with a best overall response of sCR, CR, VGPR, or PR, as determined by the investigator according to standard IMWG for MM response criteria | From baseline tumor assessment up to approximately 2 years after last dose of FT538 | 
| Duration of response (DOR) of FT538 in combination with daratumumab or elotuzumab in r/r MM | Defined as the duration from the first occurrence of a documented objective response until the time of disease progression or relapse, or death due to progressive disease, as determined by the investigator according to standard IMWG response criteria | Up to 15 years | 
| Progression-free survival (PFS) of FT538 in combination with daratumumab or elotuzumab in r/r MM | Defined as the time from first dose of study treatment to disease progression or relapse, or to the day of death from any cause, as determined by the investigator according to standard IMWG response criteria | Up to 15 years | 
| Relapse-free survival (RFS) of FT538 as monotherapy in r/r AML and in combination with daratumumab or elotuzumab in r/r MM | Defined as the time from initial CR (including CRMRD-, CR, and CRi) to hematologic relapse or death due to any cause, as determined by the investigator according to 2017 ELN criteria for AML, and defined as the duration from the start of sCR or CR until the time of relapse from sCR or CR, as determined by the investigator according to standard IMWG response criteria for MM | Up to 15 years | 
| Event-free survival (EFS) of FT538 as monotherapy in r/r AML | defined as the time from first dose of lympho-conditioning to the date of PD, or relapse from CR or CRi, or death from any cause, according to 2017 ELN criteria | Up to 15 years | 
| Overall survival (OS) of FT538 as monotherapy in r/r AML and in combination with daratumumab or elotuzumab in r/r MM | defined as the time from first dose of lympho-conditioning to death from any cause | Up to 15 years | 
| Time-to-best response of FT538 as monotherapy in r/r AML | defined as the time from first dose of lympho-conditioning to best response | Up to 15 years | 
| Determination of the pharmacokinetics (PK) of FT538 cells in peripheral blood | The PK of FT538 in peripheral blood will be reported as the relative percentage of product (FT538) DNA versus patient DNA (% chimerism) measured from blood samples at the specified time points | Study Days: 1, 2, 4, 8, 11, 15, 18, 22, 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, Acute Myeloid Leukemia, Multiple Myeloma, daratumumab, elotuzumab, NK cell, cellular therapy, allogeneic cell therapy, allogeneic cellular therapy, CD38, Anti-CD38