Clinical trial NCT06557265: NKX019, Intravenous Allogeneic Chimeric Antigen Receptor Natural Killer Cells (CAR NK), in Adults With Autoimmune Disease (Ntrust-1)
Official title: A Phase 1 Study of NKX019, a CD19 Chimeric Antigen Receptor Natural Killer (CAR NK) Cell Therapy, in Subjects With Autoimmune Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Lupus Nephritis
Glomerulonephritis
Primary Membranous Nephropathy
Keywords: CD19
CAR
Allogeneic
NKX019
Interleukin 15
Cell Therapy
Immunotherapy
Adoptive cell therapy
Lupus Nephritis
Ntrust-1
LN
Primary Membranous Nephropathy
pMN
Lead sponsor: Nkarta, Inc.
Sponsor class: INDUSTRY
First posted: 2024-08-16
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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).

Detailed description: 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 (\<92% oxygen saturation via pulse oximetry) on room air, or significant smoking history (i.e. \>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

Primary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: From the first administration of NKX019 until the last administration of any study treatment + 30 days
measure: Incidence of dose-limiting toxicities (DLTs) [Safety and Tolerability]
timeFrame: The first 29 days after the first NKX019 dose
Secondary outcomes:
measure: LN only: Number of participants who achieved complete renal response (CRR) and partial renal response (PRR)
timeFrame: Up to 2 years after NKX019 infusion
measure: LN only: Change from baseline in titer of anti-double-stranded DNA (anti-dsDNA) antibodies levels
timeFrame: Up to 2 years after NKX019 infusion
measure: LN only: Change from baseline in complement levels
timeFrame: Up to 2 years after NKX019 infusion
measure: LN only: Assessment of Lupus Low Disease Activity State (LLDAS) and Definition of Remission in SLE (DORIS) remission
timeFrame: Up to 2 years from NKX019 infusion
measure: LN only: Change from baseline in Systemic Lupus Erythematosus (SLE) Disease Activity Index 2000 (SLEDAI-2K) score
timeFrame: Up to 2 years from NKX019 infusion
measure: pMN only: Number of participants who achieved complete remission (CR) and partial remission (PR) (Couser 2017)
timeFrame: Up to 2 years from NKX019 infusion
measure: pMN only: Change from baseline in titer of anti-phospholipase A2 receptor (PLA2R) antibodies
timeFrame: Up to 2 years after NKX019 infusion
measure: pMN only: Change from baseline in serum albumin
timeFrame: Up to 2 years after NKX019 infusion
measure: pMN only: % change from baseline in estimated glomerular filtration rate (eGFR)
timeFrame: Up to 2 years after NKX019 infusion
measure: Maximum Concentration (Cmax) of NKX019 in peripheral blood
timeFrame: Up to 2 years after NKX019 infusion
measure: Time to Cmax (Tmax) of NKX019 in peripheral blood
timeFrame: Up to 2 years after NKX019 infusion
measure: Area Under the Concentration-time Curve (AUC) of NKX019 in peripheral blood
timeFrame: Up to 2 years after NKX019 infusion
measure: Half-life (t1/2) of NKX019 in peripheral blood
timeFrame: Up to 2 years after NKX019 infusion
measure: Duration of Persistence of NKX019 in peripheral blood
timeFrame: Up to 2 years after NKX019 infusion
measure: Incidence of positive anti-NKX019 antibodies to assess immunogenicity of NKX019 over time
timeFrame: Up to 2 years after NKX019 infusion
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Nkarta Investigational Site
state: Arkansas
city: Gainesville
country: United States
facility: Nkarta Investigational Site
state: Florida
city: Miami
country: United States
facility: Nkarta Investigational Site
state: Florida
city: Atlanta
country: United States
facility: Nkarta Investigational Site
state: Georgia
city: Chicago
country: United States
facility: Nkarta Investigational Site
state: Illinois
city: New Orleans
country: United States
facility: Nkarta Investigational Site
state: Louisiana
city: Worcester
country: United States
facility: Nkarta Investigational Site
state: Massachusetts
city: New York
country: United States
facility: Nkarta Investigational Site
state: New York
city: Stony Brook
country: United States
facility: Nkarta Investigational Site
state: New York
city: Dallas
country: United States
facility: Nkarta Investigational Site
state: Texas
city: Houston
country: United States
facility: Nkarta Investigational Site
state: Texas
Study officials:
affiliation: Nkarta, Inc.
name: David Shook, MD
role: STUDY_DIRECTOR
References: