Multiple Myeloma, Myeloma
Conditions
Keywords
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
Brief summary
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.
Interventions
DRUGFT576 (Allogenic CAR NK cells with BCMA expression)
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).
DRUGCyclophosphamide
Conditioning Agent
DRUGFludarabine
Conditioning Agent
DRUGDaratumumab
Anti-CD38 Monoclonal Antibody
DRUGBendamustine
Conditioning Agent
Sponsors
Fate Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 - A4 only: MM relapsed or progressed after ≥3 prior approved therapies, including an IMiD, proteosome inhibitor, and anti-CD38 mAb * Regimens B - B4 only: 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 inhaled 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: \- 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 (e.g., anti-CD38 mAbs or anti-SLAMF7 monoclonal antibodies), 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).
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| Relapse-free survival (RFS) from complete response (CR) | Up to 15 years | 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 |
| Objective response rate (ORR) | From baseline tumor assessment up to approximately 2 years after last dose of FT576 | 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 |
| Pharmacokinetics (PK) of FT576 | 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) | Concentration of FT576 in peripheral blood following FT576 administration |
| Overall survival (OS) | Up to 15 years | Time from first dose of study treatment to death from any cause |
| Duration of response (DOR) | Up to 15 years | 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 |
| Progression-free survival (PFS) | Up to 15 years | 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 |
Countries
United States
Outcome results
None listed