FT576 in Subjects With Multiple Myeloma

Study Overview
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Brief Summary
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This is a Phase I dose-finding study of FT576 as monotherapy and in combination with the monoclonal antibody daratumumab in multiple myeloma (MM). The study will consist of a dose-escalation stage and an expansion stage.

Official Title
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A Phase I Study of FT576 as Monotherapy and in Combination With Daratumumab in Subjects With Relapsed/Refractory Multiple Myeloma

Conditions
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Multiple Myeloma, Myeloma

Intervention / Treatment
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* Drug: FT576 (Allogenic CAR NK cells with BCMA expression)
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Daratumumab
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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Abbreviated inclusion criteria: Diagnosis of r/r MM with measurable disease by at least one of the following: Serum M-protein ≥1.0 g/dL Urine M-protein ≥200 mg/24 hours Involved serum free light chain level ≥10 mg/dL, with an abnormal kappa-lambda ratio if the serum M-protein <1.0 g/dL and/or urine M-protein <200 mg/24 hours Regimens A and A1: MM relapsed or progressed after ≥3 prior approved therapies, including an IMiD, proteosome inhibitor, and anti-CD38 mAb Regimens B and B1: MM relapsed or progressed after ≥2 prior approved therapies, including an IMiD and proteosome inhibitor Note: for all Regimens, prior BCMA CAR T-cell therapy and BCMA-targeted therapy (e.g., bi-specific engagers or antibody-drug conjugates) is allowed * Abbreviated exclusion criteria: Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2 Evidence of insufficient hematologic function: ANC <1000/µL without growth factor support ≤7 days prior to measurement Platelet count <75,000/µL without platelet transfusion ≤72 hours prior to measurement Evidence of insufficient organ function CrCL <50 ml/min by Cockcroft-Gault or other institutional method T bilirubin >1.5x ULN, except for Gilbert's syndrome AST >3x ULN or ALT >3x ULN, unless directly due to underlying malignancy O2 sat <92% on room air Clinically significant cardiovascular disease: Myocardial infarction within 6 months of first treatment Unstable angina or CHF of NYHA Grade 2 or higher Cardiac EF <40% Subjects with active central nervous system (CNS) , including leptomeningeal disease. Subjects with prior CNS involvement may be enrolled into the study if effective treatment of their CNS disease was completed at least 3 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 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 immunosuppressive therapy (e.g., prednisone >5 mg daily) for any reason during the treatment period, with the exception of corticosteroids. Clinically significant infections, including: HIV positive by serology HBV positive by serology or PCR HCV positive by serology or PCR Live vaccine <6 weeks prior to start of conditioning Receipt of an allograft organ transplant Ongoing requirement for systemic graft -versus-host disease therapy Plasma cell leukemia defined as a plasma cell count >2000/mm^3 Prior malignancy (other than current indication including any antecedent hematologic disorder) within the 2 years prior to enrollment except for the following: basal or squamous cell carcinomas of the skin, carcinoma in situ of the cervix or breast treated with curative intent, or localized prostate cancer treated with curative intent, or malignancy that, in the opinion of the investigator and Sponsor's Medical Monitor, is considered cured with minimal risk of recurrence within 3 years. Washout periods from prior therapies: For all subjects (Regimens A, A1, B and B1), receipt of the following: Chemotherapy, or radiation therapy, except for palliative purposes, within 14 days prior to the first dose of FT576 (Day 1) or five half-lives, whichever is shorter; Investigational therapy within 30 days prior to the first dose of FT576 study treatment or five half-lives, whichever is shorter; Biologic therapy (except for anti-CD38 mAbs in Regimen B and B1), including autologous cellular immunotherapy (e.g. CAR-T/ CAR-NK), antibody-drug conjugates or bi-specific immune-cell engaging antibody within 30 days prior to first dose of FT576 (Day 1) or half -lives whichever is shorter. prior allogenic HSCT or allogenic CAR-T/CAR-NK within 6 months of first dose of FT576 (Day1). For subjects in Regimens B and B1 only, receipt of the following: Anti-CD38 therapy alone or in combination within 3 months prior to the start of daratumumab

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: Regimen A<br>FT576 single dose monotherapy in subjects with r/r MM | Drug: FT576 (Allogenic CAR NK cells with BCMA expression)<br>* Experimental Interventional Therapy: FT576 comprises allogeneic natural killer (NK) cells, derived from a clonal, CD38-knockout, human-induced pluripotent stem cell line (iPSC) that expresses anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR), high-affinity, non-cleavable CD16 (hnCD16), and IL-15/IL-15 receptor fusion protein (IL-15RF).<br>Drug: Cyclophosphamide<br>* Conditioning Agent<br>Drug: Fludarabine<br>* Conditioning Agent<br>Drug: Bendamustine<br>* Conditioning Agent<br>* Other names: Treanda;|
| Experimental: Regimen A1<br>FT576 multiple dose monotherapy in subjects with r/r MM | Drug: FT576 (Allogenic CAR NK cells with BCMA expression)<br>* Experimental Interventional Therapy: FT576 comprises allogeneic natural killer (NK) cells, derived from a clonal, CD38-knockout, human-induced pluripotent stem cell line (iPSC) that expresses anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR), high-affinity, non-cleavable CD16 (hnCD16), and IL-15/IL-15 receptor fusion protein (IL-15RF).<br>Drug: Cyclophosphamide<br>* Conditioning Agent<br>Drug: Fludarabine<br>* Conditioning Agent<br>Drug: Bendamustine<br>* Conditioning Agent<br>* Other names: Treanda;|
| Experimental: Regimen B<br>FT576 single dose in combination with daratumumab in subjects with r/r MM | Drug: FT576 (Allogenic CAR NK cells with BCMA expression)<br>* Experimental Interventional Therapy: FT576 comprises allogeneic natural killer (NK) cells, derived from a clonal, CD38-knockout, human-induced pluripotent stem cell line (iPSC) that expresses anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR), high-affinity, non-cleavable CD16 (hnCD16), and IL-15/IL-15 receptor fusion protein (IL-15RF).<br>Drug: Cyclophosphamide<br>* Conditioning Agent<br>Drug: Fludarabine<br>* Conditioning Agent<br>Drug: Daratumumab<br>* Anti-CD38 Monoclonal Antibody<br>* Other names: Darzalex Faspro;Drug: Bendamustine<br>* Conditioning Agent<br>* Other names: Treanda;|
| Experimental: Regimen B1<br>FT576 multiple dose in combination with daratumumab in subjects with r/r MM | Drug: FT576 (Allogenic CAR NK cells with BCMA expression)<br>* Experimental Interventional Therapy: FT576 comprises allogeneic natural killer (NK) cells, derived from a clonal, CD38-knockout, human-induced pluripotent stem cell line (iPSC) that expresses anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR), high-affinity, non-cleavable CD16 (hnCD16), and IL-15/IL-15 receptor fusion protein (IL-15RF).<br>Drug: Cyclophosphamide<br>* Conditioning Agent<br>Drug: Fludarabine<br>* Conditioning Agent<br>Drug: Daratumumab<br>* Anti-CD38 Monoclonal Antibody<br>* Other names: Darzalex Faspro;Drug: Bendamustine<br>* Conditioning Agent<br>* Other names: Treanda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and nature of DLTs within each dose-escalation cohort to determine the MTD or MAD |  | Cycle 1 Day -5 to Day 29 for Regimen A and A1; Cycle 1 Day -11 to Day 29 (each cycle is 40 days) for Regimen B and B1 | 
| Determine the RP2D which will be based on the overall safety and anti-tumor activity among the dose escalation and dose expansion cohorts |  | From FPI to LPI's end of Cycle 1 study treatment (End of cycle is Day 29 from Day 1 FT576 infusion) | 
| Incidence, nature, and severity of adverse events |  | Cycle 1 Day -5 to Day 29 for Regimen A and A1; Cycle 1 Day -11 to Day 29 (each cycle is 40 days) for Regimen B and B1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Proportion of subjects with a best overall response of sCR, CR, VGPR, or PR, as determined by the investigator according to standard IMWG response criteria | From baseline tumor assessment up to approximately 2 years after last dose of FT576 | 
| Duration of response (DOR) | 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) | 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) from complete response (CR) | 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 | Up to 15 years | 
| Overall survival (OS) | Time from first dose of study treatment to death from any cause | Up to 15 years | 
| Pharmacokinetics (PK) of FT576 | Concentration of FT576 in peripheral blood following FT576 administration | From Baseline to PTFU visit of last cycle on the study treatment (End of cycle is Day 29 from Day 1 FT576 infusion of this cycle) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, daratumumab, CAR NK cell, cellular therapy, relapsed/refractory multiple myeloma, allogeneic natural killer cells, anti-CD38 monoclonal antibody, chimeric antigen receptor (CAR), BCMA, anti-B-cell maturation antigen (BCMA), natural killer (NK) cell