nkx019, intravenous allogeneic chimeric antigen receptor natural killer cells (car nk), in adults with autoimmune disease (ntrust-1)

Conditions: Lupus Nephritis; Glomerulonephritis; Primary Membranous Nephropathy

Summary: this is an open-label, multi-center, non-randomized phase 1 study to determine the safety and tolerability of nkx019 (allogeneic car nk cells targeting cd19) in participants with active lupus nephritis (ln) or primary membranous nephropathy (pmn).

this is a dose-finding study of nkx019 and will be conducted in 2 parts: part 1 dose escalation will utilize a "3+3" design to determine the recommended dose for expansion for part 2. the study will evaluate safety and tolerability, preliminary activity, cellular kinetics, pharmacodynamics in participants with active ln or pmn. participants will receive a cycle consisting of lymphodepletion with fludarabine and cyclophosphamide (flu/cy), followed by three doses of nkx019. participants who are cytopenic may receive a modified ld regimen of cy alone.

Eligibility criteria:
general inclusion criteria: 1. age ≥18 and ≤65 2. progression despite maximal tolerated doses of renin-angiotensin system (ras) blockade agents 3. for participants taking chronic corticosteroids for management of the disease under study, stable dose for ≥ 14 days before the screening visit with planned reduction to ≤ 5 mg prednisone by the time of ld start 4. negative sars-cov-2 test ln-specific inclusion criteria: 1. score of 10 or more points on the american college of rheumatology (acr) 2019 classification criteria for sle 2. active nephritis class iii, iv, and/or v using the 2018 international society of nephrology and renal pathology society (isn/rps) criteria (bajema 2018) as evidenced on kidney biopsy during screening or within 6 months before screening. per nih indices, subjects must have at least moderate activity score and no more than moderate chronicity index 3. active renal disease as defined by urinary protein:creatinine ratio (upcr) ≥ 1.5 g/g or proteinuria ≥1.5 g/day and ≤ 7 g/day 4. positive antinuclear antibodies (ana) ≥ 1:80 or anti-dsdna or anti-smith (anti-sm) 5. refractory ln defined as having received ≥ 2 prior therapies for ln pmn-specific inclusion criteria: 1. evidence of pmn by renal biopsy during screening or within 6 months before screening 2. active renal disease at screening defined by upcr ≥ 3.5 g/g or proteinuria ≥ 3.5 g/day 3. positive anti-pla2r antibodies 4. refractory or intolerant to either b cell-depleting agents and/or cyclophosphamide and/or calcineurin inhibitors defined as not achieving a complete remission after 180 days, or partial remission after 90 days general exclusion criteria: 1. egfr \< 45 ml/min/1.73 m\^2 2. currently requiring renal dialysis or expected to require dialysis during the study period 3. previous solid organ or hematopoietic cell transplant or planned transplant within study treatment period 4. congenital or acquired immunodeficiency resulting in severe infection or those receiving chronic immunoglobulin replacement therapy 5. liver disease or dysfunction, including cirrhosis and/or aspartate aminotransferase, alanine aminotransferase, or bilirubin ≥ 3 times the upper limit of normal 6. pulmonary comorbidity including chronic obstructive pulmonary disease or asthma requiring daily oral steroids, resting hypoxemia (\ 10 pack/year) 7. white blood cell count \< 3,000/mm\^3; hemoglobin levels \< 9 gm/dl absolute neutrophil count \< 2,000/mm\^3; platelet count \< 100,000/mm\^3 8. major cardiac disease, abnormalities, or interventions as defined by, but not limited to: 1. uncontrolled angina or unstable life-threatening arrhythmias 2. history of myocardial infarction within 12 weeks prior to the first dose of nkx019 3. any prior coronary artery bypass graft surgery 4. ≥ class iii new york heart association (nyha) congestive heart failure (chf), significantly decreased ejection fraction (ef ≤ 40%), or severe cardiac insufficiency. 5. prolongation of the qt interval corrected for heart rate (qtc) (fridericia) interval of \> 480 msec 6. peripheral artery bypass graft surgery, pulmonary embolism, or other ≥ grade 2 thrombotic or embolic events within 12 weeks prior to the first dose of nkx019 7. uncontrolled hypertension (systolic blood pressure \> 160mmhg and diastolic \> 90mmhg) despite therapy 9. active bleeding disorders 10. any overlapping autoimmune condition for which the condition itself or the treatment of that condition may affect the study assessments or outcomes; conditions that could cause a secondary nephropathy; or kidney biopsy-confirmed significant renal disease other than disease under study 11. pregnancy, breast feeding or, if of childbearing potential, not using adequate contraceptive precautions 12. current infection requiring active systemic anti-infective therapy or recent acute infection requiring systemic therapy within 30 days of planned ld 13. history of positive hiv antibody or test positive at screening, hepatitis b or c positive at screening, active tuberculosis (tb) or latent tb requiring suppressive therapy 14. malignancy within 5 years of screening, with the exception of basal and squamous cell carcinomas treated by complete excision. subjects with cervical dysplasia that is cervical intraepithelial neoplasia but have been treated with conization or loop electrosurgical excision procedure and have had a normal repeat papanicolaou test are allowed 15. prior cellular therapy 16. central nervous system (cns) comorbidity or any autoimmune disease with cns involvement within 90 days prior to the first dose of nkx019 as well as active cns lupus within 1 year prior to screening 17. any other acute or chronic medical or psychiatric condition, or known laboratory abnormality that, in the investigator's opinion, is expected to interfere or impact study participation 18. prior immunosuppressive/immunomodulating therapies, including investigational agents, within 14 days or 5 half-lives of the drug (whichever is shorter), prior to ld. note: prior antibody therapies not allowed within 90 days of ld 19. currently taking or known need for any of the medications prohibited in the study protocol 20. known hypersensitivity or contraindications to the study treatment including ld; or other components such as human serum albumin or dimethyl sulfoxide ln-specific exclusion criteria: 1. known antiphospholipid antibody syndrome (aps); or high-risk profile

Keywords: cd19 car allogeneic nkx019 interleukin 15 cell therapy immunotherapy adoptive cell therapy lupus nephritis ntrust-1 ln primary membranous nephropathy pmn