Granulomatosis With Polyangiitis, Pemphigus Vulgaris, Rheumatoid Arthritis, Systemic Lupus Erythematosus
Conditions
Brief summary
This study will evaluate the safety and activity of AB-101 in combination with rituximab in B-cell associated autoimmune diseases where rituximab is currently FDA approved (e.g., Rheumatoid Arthritis (RA), Pemphigus Vulgaris (PV), Granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA) as a therapeutic, or is recommended (e.g., in Systemic Lupus Erythematosus (SLE) as a cornerstone for disease management.
Interventions
DRUGAB-101
Subjects in all 4 indications will receive only one cycle of treatment. Subjects with RA, PV or SLE will receive one cycle of treatment as follows: 1. Fludarabine: 25 mg/m2 on Day 1, Day 2 and Day 3. 2. Cyclophosphamide: 1000 mg/m2 on Day 3 3. Rituximab: 1000 mg on Day 1 and Day 15 4. AB-101: 1B NK cells (AlloNK) on Day 6, Day 13 and Day 20 Subjects with GPA and MPA will receive one cycle of treatment as follows: 1. Fludarabine: 25 mg/m2 on Day 1, Day 2, and Day 3. 2. Cyclophosphamide: 1000 mg/m2 on Day 3 3. Rituximab: 375 mg/m2 on Day -2, Day 6, Day 13, and Day 20 4. AB-101: 1B NK cells (AlloNK) on Day 6, Day 13, and Day 20 The first dose of AB-101 should be administered at least 48 hours after the last infusion of the lymphodepletion regimen.
DRUGRituximab
Subjects in all 4 indications will receive only one cycle of treatment. Subjects with RA, PV or SLE will receive one cycle of treatment as follows: 1. Fludarabine: 25 mg/m2 on Day 1, Day 2 and Day 3. 2. Cyclophosphamide: 1000 mg/m2 on Day 3 3. Rituximab: 1000 mg on Day 1 and Day 15 4. AB-101: 1B NK cells (AlloNK) on Day 6, Day 13 and Day 20 Subjects with GPA and MPA will receive one cycle of treatment as follows: 1. Fludarabine: 25 mg/m2 on Day 1, Day 2, and Day 3. 2. Cyclophosphamide: 1000 mg/m2 on Day 3 3. Rituximab: 375 mg/m2 on Day -2, Day 6, Day 13, and Day 20 4. AB-101: 1B NK cells (AlloNK) on Day 6, Day 13, and Day 20 The first dose of AB-101 should be administered at least 48 hours after the last infusion of the lymphodepletion regimen.
DRUGCyclophosphamide
Subjects in all 4 indications will receive only one cycle of treatment. Subjects with RA, PV or SLE will receive one cycle of treatment as follows: 1. Fludarabine: 25 mg/m2 on Day 1, Day 2 and Day 3. 2. Cyclophosphamide: 1000 mg/m2 on Day 3 3. Rituximab: 1000 mg on Day 1 and Day 15 4. AB-101: 1B NK cells (AlloNK) on Day 6, Day 13 and Day 20 Subjects with GPA and MPA will receive one cycle of treatment as follows: 1. Fludarabine: 25 mg/m2 on Day 1, Day 2, and Day 3. 2. Cyclophosphamide: 1000 mg/m2 on Day 3 3. Rituximab: 375 mg/m2 on Day -2, Day 6, Day 13, and Day 20 4. AB-101: 1B NK cells (AlloNK) on Day 6, Day 13, and Day 20 The first dose of AB-101 should be administered at least 48 hours after the last infusion of the lymphodepletion regimen.
DRUGFludarabine
Subjects in all 4 indications will receive only one cycle of treatment. Subjects with RA, PV or SLE will receive one cycle of treatment as follows: 1. Fludarabine: 25 mg/m2 on Day 1, Day 2 and Day 3. 2. Cyclophosphamide: 1000 mg/m2 on Day 3 3. Rituximab: 1000 mg on Day 1 and Day 15 4. AB-101: 1B NK cells (AlloNK) on Day 6, Day 13 and Day 20 Subjects with GPA and MPA will receive one cycle of treatment as follows: 1. Fludarabine: 25 mg/m2 on Day 1, Day 2, and Day 3. 2. Cyclophosphamide: 1000 mg/m2 on Day 3 3. Rituximab: 375 mg/m2 on Day -2, Day 6, Day 13, and Day 20 4. AB-101: 1B NK cells (AlloNK) on Day 6, Day 13, and Day 20 The first dose of AB-101 should be administered at least 48 hours after the last infusion of the lymphodepletion regimen.
Sponsors
Artiva Biotherapeutics, Inc.
IRIS Research and Development, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label Single-Center Study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
General Inclusion Criteria (applicable to subjects in all 4 studied indications) 1. Males or female subjects, ≥ 18 years of age at the time of signing informed consent. 2. Ability to understand the requirements of the study. 3. Willingness to provide written informed consent. 4. Willingness to comply with the study protocol procedures. 5. Women of childbearing potential and all male participants must agree to use two acceptable methods of contraception together to avoid pregnancy. The following are examples of acceptable methods of contraception including: 1. Established use of oral, inserted, injected, or implanted hormonal methods of contraception. 2. Correctly placed copper containing intrauterine device (IUD). 3. Male condom or female condom used WITH a spermicide (i.e., foam, gel, film, cream, suppository). 4. Male sterilization with appropriately confirmed absence of sperm in the post-vasectomy ejaculate. 5. Bilateral tubal ligation or bilateral salpingectomy. 6. Oral steroids will be tapered to \<20 mg/day of prednisone (or equivalent) at least 1 week prior to the first study treatment. The tapering schedule will be at the discretion of the Investigator. 7. Subjects must have a predicted diffusing capacity for carbon monoxide (DLCO) of \>60% and a forced expiratory volume 1 (FEV1) \>70% at screening. 8. Left ventricular ejection fraction (LVEF) ≥ 45% by Echocardiogram. Rituximab and AB-101 in autoimmune diseases Clinical Study Protocol V. 1.1 Confidential Page 11 of 101 April 16, 2024 9. Baseline laboratory values fulfilling the following requirements to demonstrate adequate hematologic, renal, and hepatic function: RA PV MPA / GPA SLE Absolute neutrophil count (/mm3) * 1500 * 1500 * 1500 * 1500 Platelets (/mm3) * 100,000 * 100,000 * 100,000 * 75,000 Hemoglobin (g/dL) * 9 * 9 * 9 * 8 Creatinine clearance (mL/min/1.73 m2) * 60 * 60 * 60 * 60 Total serum bilirubin (mg/dL) \< 2.5 \< 2.5 \< 2.5 \< 2.5 Liver transaminases (AST/ALT/ALP) ≤ 3x ULN ≤ 3x ULN * 3x ULN * 3x ULN Additional Disease-specific Inclusion Criteria Rheumatoid Arthritis 1\. Documented diagnosis of RA, meeting the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA (Kay, 2012). 2\. Have had prior treatment for a period of at least 12 weeks with a biologic disease-modifying anti-rheumatic drugs (bDMARD e.g., infliximab, rituximab, etanercept, tocilizumab)) and/or a targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARD e.g., baricitinib, tofacitinib)) and were deemed refractory by either: 1. In the opinion of the Investigator, there was a lack of benefit to at least two bDMARDs or one bDMARD and one tsDMARDs. Lack of benefit may include inadequate improvement in joint counts, physical function, or disease activity. 2. Intolerance to at least two lines of prior therapy, including bDMARDs and/or tsDMARDs. 3\. Minimum of 6 swollen joint counts (SJC) and 6 tender joint counts (TJC). Pemphigus Vulgaris 1. Confirmed diagnosis of pemphigus vulgaris with active lesions. 2. Positive for anti-desmoglein Dsg1 or Dsg3. 3. Pemphigus Disease Area Index score of \> 10%. 4. Subjects will have tried and failed at least 12 weeks of treatment of immunosuppressive or biologic standard-of-care agent (methotrexate, azathioprine, mycophenolate mofetil (MMF) or mycophenolic acid (MPA) and corticosteroids, and/or 12 weeks of therapy with IV Gamma globulin treatments with an exposure of 12 weeks to be considered resistant/refractory and will be included in this study. Granulomatosis with polyangiitis (GPA) / microscopic polyangiitis (MPA) <!-- --> 1. Clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). 2. Presence of cytoplasmic Antineutrophil cytoplasmic antibody (c-ANCA) or proteinase-3 (PR3-ANCA) or myeloperoxidase ANCA (MPO-ANCA) 3. Have ≥ 1 major item, or ≥ 3 other items, or ≥ 2 renal items on the Birmingham Vasculitis Activity Score Version 3 (BVASv3). 4. For GPA/MPA, subjects will have tried and failed at least 12 weeks of treatment of immunosuppressive (Cyclophosphamide, mycophenolate mofetil (MMF) or mycophenolic acid (MPA) and corticosteroids), or a biologic standard-of-care agent such as Rituximab will be included in this study. Systemic Lupus Erythematous 1. Diagnosis of SLE according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) Classification Criteria. 2. Total systemic lupus erythematosus disease activity index (SLEDAI-2K) ≥ 8 at screening excluding alopecia, mucosal ulcers, and fever. 3. Positive for anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies. 4. For SLE, subjects will have tried and failed at least 12 weeks of 2 conventional therapies which, at the discretion of the investigator, includes antimalarials, corticosteroids, immunosuppressive agents, such as mycophenolate mofetil, Methotrexate, Azathioprine, as well as biologic agents such as Belimumab, Anifrolumab, and Rituximab. The following criteria for standard-of-care therapies must be met: <!-- --> 1. If receiving antimalarial drugs (e.g., hydroxychloroquine, chloroquine, quinacrine), must have used the medication for ≥ 12 weeks prior to first study treatment and at a stable dose for a minimum of 6 weeks prior to first administration of AB-101. 2. If receiving immunomodulatory drugs (mycophenolate mofetil \[MMF\]/mycophenolic acid ≤ 2 g/day, azathioprine/6 mercaptopurine (AZA/6 MP) ≤ 2 mg/kg/day, leflunomide ≤ 40 mg/day, methotrexate (MTX) ≤ 25 mg/wk with concomitant folic acid \[recommend ≥ 5 mg/wk\]), calcineurin inhibitor, and/or cyclosporin A, receiving a stable dose for at least 12 weeks prior to the first administration of AB-101. Oral corticosteroid (OCS) \<20 mg/day prednisone or equivalent started at least 12 weeks prior to first study treatment and at a stable dose for at least 4 weeks prior to first administration of study treatment. It must be planned that the background standard-of-care treatment remains at a stable dose throughout the Screening Period.
Exclusion criteria
General
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Serious Adverse Events (SAE) and causality assessment | From the time of consent through 104 weeks after initiation of study treatment | We will evaluate the Incidence of adverse events and relationship to study drug |
| Incidence of adverse events and relationship to study drug | From the time of consent through 104 weeks after initiation of study treatment | We will evaluate the Incidence of adverse events and relationship to study drug |
| Total hospitalizations, duration of hospitalizations through the course of the study | From the time of consent through 104 weeks after initiation of study treatment | We will evaluate the Incidence of adverse events and relationship to study drug |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SLE: Change from baseline in the SLE Disease Activity Index (SLEDAI) at Week 12 and 24 | Week 12 through 24 | SLE: Change from baseline in the SLE Disease Activity Index (SLEDAI) at Week 12 and 24 |
| GPA / MPA: Change from baseline in the Birmingham Vasculitis Activity Score at Week 12 and 24 | Week 12 through 24 | GPA / MPA: Change from baseline in the Birmingham Vasculitis Activity Score at Week 12 |
| PV: Change from baseline in the Pemphigus Disease Area Index (PDAI) at Week 12 and 24 | Week 12 through 24 | PV: Change from baseline in the Pemphigus Disease Area Index (PDAI) at Week 12 and 24 |
| RA: Change From Baseline in DAS28 at Week 12 and 24 | Week 12 through 24 | RA: Change From Baseline in DAS28 at Week 12 and 24 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics and Immunogenicity | at baseline and according to the scheduled of assessments | Blood samples for pharmacokinetic analysis and immunogenicity will be collected according to the SoA |
| Pharmacodynamic Biomarkers | from the time of consent through 104 weeks after initiation of styudy treatment | The following biomarkers will be measured at baseline and according to the scheduled of assessments. Autoantibodies: ANA, anti-dsDNA, aCL (IgG, IgM, IgA isotypes), anti-Sm, and anti- C1q 2. Serum immunoglobulin isotypes: IgA, IgG, IgM 3. Serum complement (C3, C4) 4. Serum cytokines/chemokines, urinary biomarkers 5. Peripheral B cell subsets, T and NK lymphocytes 6. DSG 1 and DSG 3 autoantibodies |
| Patient Reported Outcomes | from the time of consent through 104 weeks after initiation of styudy treatment | Patient Reported Outcomes |
Countries
United States
Contacts
Primary ContactKathy I Perez, M.D.
Backup ContactJhon Galindo, B.S.
Outcome results
None listed