A Study to Evaluate the Safety and Preliminary Efficacy of ATA3219 in Participants With Lupus Nephritis

Systemic Lupus Erythematosus Clinical Trial

Official title:

A Phase 1 Study to Evaluate the Safety and Preliminary Efficacy of ATA3219, Allogeneic Anti-CD19 Chimeric Antigen Receptor T-cell (CAR T) Therapy, in Subjects With Lupus Nephritis

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06429800
• Other study ID #: ATA3219-AEC-104
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: October 31, 2024
• Est. completion date: April 2029

Study information

• Verified date: May 2024
• Source: Atara Biotherapeutics
• Contact: Study Director
• Phone: 650-278-8930
• Email: clinicalstudies[@]atarabio.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to evaluate the safety and preliminary efficacy of ATA3219 (following lymphodepletion) for treatment of participants with lupus nephritis (LN).

Description:

This is a Phase 1, multi-centered, open-labeled, dose escalation study to evaluate the safety and preliminary efficacy of ATA3219 (as monotherapy) in participants with LN. Up to 3 dose levels (DLs) will be explored in the dose escalation portion of the study and if needed a lower dose may be explored. Prior to undergoing any screening procedure, prospective participants must undergo the ATA3219 inventory check assessments to ensure availability of an appropriate partially human leukocyte antigen (HLA)-matched ATA3219 lot. Before administration of ATA3219, participants will receive conditioning chemotherapy. For all enrolled participants, hospitalization during and following ATA3219 dosing is mandatory. Participants will receive a single dose intravenous (IV) infusion of ATA3219 (monotherapy) on Day 1. Participants will remain inpatient for a minimum of 1 week post ATA3219 dosing, where they will be frequently monitored. Lupus nephritis activity will be assessed by the investigator on Day 28 (+ 5 days) following each dose of ATA3219. During dose escalation, up to 3 dose levels of ATA3219 are planned to be evaluated sequentially and a lower dose may be added. At least 3 and up to 6 dose-limiting toxicity (DLT)-evaluable participants, those who complete the 28-day DLT observation period, will be assessed at each dose level. Within each dose level, treatment will be staggered to allow appropriate safety monitoring by an independent Data Safety Monitoring Committee (DSMC).

Participants who do not receive ATA3219 for any cause may be replaced. Participants who experience an adverse event (AE) prior to completion of the 28-day DLT observation period will not be replaced. If a participant is treated with ATA3219 and discontinues for any reason other than a DLT prior to completing the 28-day DLT observation period, an additional participant may be enrolled at the dose level to ensure that the recommended phase 2 dose (RP2D) can be determined. In rare situations, retreatment of participants with inadequate renal response may be considered.

After treatment is completed or discontinued, participants will be followed for safety and renal response for up to 24 months from the last dose of ATA3219. A separate long-term follow-up study will be conducted to follow participants for up to a total of 15 years after their last dose of ATA3219.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 26
• Est. completion date: April 2029
• Est. primary completion date: October 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

1. Diagnosed with SLE according to the 2019 European League Against Rheumatism/American College of Rheumatology classification for SLE or the Systemic Lupus International Collaborating Clinics Classification criteria [Petri 2012].

2. Meets one or more of the following immunologic criteria during screening:

1. Anti double stranded DNA above laboratory reference range, except enzyme linked immunosorbent assay (2 × above laboratory reference range), OR

2. Presence of anti-Smith antibody, OR

3. Low complement as demonstrated by low complement component 3, low complement component 4, or low complement CH50.

3. History of International Society of Nephrology/Renal Pathology Society (ISN/RPS) Class III or IV with or without Class V glomerulonephritis on renal biopsy either within 6 months prior to screening or as performed during screening. Biopsy should demonstrate evidence of active nephritis.

4. Proteinuria level between = 1.0 to 6.0 g/day via urine protein creatinine ratio during screening.

5. Has refractory LN defined as having received 1 or more standard therapies for LN (which must have included mycophenolate mofetil, mycophenolic acid, or cyclophosphamide), and:

1. Has worsening LN (per criteria listed in [Gordon 2009]) while on treatment, OR

2. Has not achieved a complete renal response (CRR) after 2 or more lines of therapy, OR

3. Has not achieved a CRR after first-line therapy after a minimum of 12 months.

6. Is using a stable, optimized dose of a renin angiotensin system inhibitor for at least 4 weeks prior to enrollment, unless deemed inappropriate by the investigator.

7. Participants must have been previously vaccinated for pneumococcus within 5 years prior to screening (and no later than 4 weeks prior to enrollment) or be willing to receive prophylaxis against infections with encapsulated bacteria via vaccination in accordance with local standards of practice and/or guidelines.

8. Is current per national or local health authority or institutional guidelines for immunocompromised individuals on the following vaccinations, unless refused or medically contraindicated: varicella zoster (Shingrix), pneumococcal, influenza, and Corona virus disease 2019 (COVID-19).

Exclusion Criteria:

1. Severe kidney disease as assessed locally, defined as history of ISN/RPS Class VI or isolated Class V glomerulonephritis (without co existent/predominant Class III or IV glomerulonephritis) on renal biopsy.

2. Has a concurrent systemic autoimmune disease that may confound study assessments other than SLE, LN, or cutaneous lupus erythematosus.

3. Has any unstable or progressive manifestation of SLE that is likely to warrant an intensification of lupus-directed therapy

4. Has a history of confirmed or suspected drug-induced lupus.

5. Has a history of catastrophic antiphospholipid syndrome, or any history of prior thrombosis due to antiphospholipid syndrome resulting in hospitalization due to myocardial infarction, pulmonary embolism, or stroke.

6. Has a history of bleeding disorder requiring hospitalization or systemic therapeutic intervention within the previous 3 months, or for participants without a prior kidney biopsy meeting eligibility criterion within the past 6 months who will require a biopsy during screening, any contraindication to kidney biopsy.

7. Severe B cell immunodeficiency as evidenced by clinically significant refractory/recurrent infection.

8. Any prior cellular therapies, obinutuzumab, anti-cluster of differentiation 19 (CD19) antibody, or B-cell targeting bispecific antibody, unless B-cells have recovered to baseline as assessed by the investigator. Investigational therapies or initiation of new SLE-directed therapies within 4 weeks.

Related Conditions & MeSH terms

• Lupus Erythematosus, Systemic
• Lupus Nephritis
• Nephritis
• Systemic Lupus Erythematosus

Intervention

Drug:
• ATA3219
ATA3219 is an allogeneic chimeric antigen receptor (CAR) T-cell therapy containing a second generation CD19 CAR construct in Epstein Barr virus (EBV) T cells, administered intravenously on Day 1.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Atara Biotherapeutics

References & Publications (2)

Gordon C, Jayne D, Pusey C, Adu D, Amoura Z, Aringer M, Ballerin J, Cervera R, Calvo-Alen J, Chizzolini C, Dayer J, Doria A, Ferrario F, Floege J, Guillevin L, Haubitz M, Hiepe F, Houssiau F, Lesavre P, Lightstone L, Meroni P, Meyer O, Moulin B, O'Reilly K, Praga M, Schulze-Koops H, Sinico R, Smith K, Tincani A, Vasconcelos C, Hughes G. European consensus statement on the terminology used in the management of lupus glomerulonephritis. Lupus. 2009 Mar;18(3):257-63. doi: 10.1177/0961203308100481. — View Citation

Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR, Bruce IN, Isenberg D, Wallace DJ, Nived O, Sturfelt G, Ramsey-Goldman R, Bae SC, Hanly JG, Sanchez-Guerrero J, Clarke A, Aranow C, Manzi S, Urowitz M, Gladman D, Kalunian K, Costner M, Werth VP, Zoma A, Bernatsky S, Ruiz-Irastorza G, Khamashta MA, Jacobsen S, Buyon JP, Maddison P, Dooley MA, van Vollenhoven RF, Ginzler E, Stoll T, Peschken C, Jorizzo JL, Callen JP, Lim SS, Fessler BJ, Inanc M, Kamen DL, Rahman A, Steinsson K, Franks AG Jr, Sigler L, Hameed S, Fang H, Pham N, Brey R, Weisman MH, McGwin G Jr, Magder LS. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012 Aug;64(8):2677-86. doi: 10.1002/art.34473. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence and severity of treatment-emergent adverse events, including adverse events of special interest		From administration of conditioning treatment through 90 days after administration of study drug
Primary	Incidence of Dose-limiting Toxicities		Day 1 through Day 28 of first dose of study drug
Primary	Maximum Tolerated dose		Day 1 through Day 28 of first dose of study drug
Primary	Recommended Phase 2 dose of ATA3219		Day 1 through Day 28 of first dose of study drug
Secondary	Maximum Observed Plasma Concentration (Cmax) of ATA3219		Pre-dose on Day 1 through 24 months after the last dose on a defined schedule
Secondary	Time to Reach Cmax (Tmax) of ATA3219		Pre-dose on Day 1 through 24 months after the last dose on a defined schedule
Secondary	Partial Area Under the Curve (pAUC) of ATA3219		Pre-dose on Day 1 through 24 months after the last dose on a defined schedule
Secondary	Last Observed Plasma Concentration (Clast) of ATA3219		Pre-dose on Day 1 through 24 months after the last dose on a defined schedule
Secondary	Time of Clast of ATA3219		Pre-dose on Day 1 through 24 months after the last dose on a defined schedule
Secondary	Terminal Half-life (t1/2) of ATA3219		Pre-dose on Day 1 through 24 months after the last dose on a defined schedule
Secondary	Complete Renal Response		Weeks 24 and 52
Secondary	Partial Renal Response		Weeks 24 and 52
Secondary	Renal Objective Response Rate		Weeks 24 and 52
Secondary	Change From Baseline in Urine protein to Creatinine Ratio		Baseline (Day -5) through 24 months after the last dose on a defined schedule
Secondary	Change From Baseline in Estimated Glomerular Filtration Rate		Baseline (Day -5) through 24 months after the last dose on a defined schedule
Secondary	Duration of Urine Protein to Creatinine ratio = 0.5		Baseline (Day -5) through 24 months after the last dose on a defined schedule
Secondary	Change From Baseline in Lupus Low Disease Activity State (LLDAS)		Baseline (Day 28) through 24 months after the last dose on a defined schedule
Secondary	Change From Baseline in Definition of Remission in Systemic Lupus Nephritis (DORIS)		Baseline (Day 28) through 24 months after the last dose on a defined schedule
Secondary	Change From Baseline in the Modified Version of the Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Nephritis Disease Activity (Hybrid SELENA-SLEDAI) Index		Baseline (Day 28) through 24 months after the last dose on a defined schedule
Secondary	Change From Baseline in British Isles Lupus Assessment Group (BILAG) Index		Baseline (Day 28) through 24 months after the last dose on a defined schedule
Secondary	Change From Baseline in Antibodies to Double Stranded Deoxyribonucleic Acid		Baseline (Day 1) through 24 months after the last dose on a defined schedule
Secondary	Change From Baseline in Complement Component 3 (C3) and Complement Component 4 (C4) Levels		Baseline (Day 1) through 24 months after the last dose on a defined schedule