2025-520461-41-00招募中2 期
An open-label Phase 2a study to evaluate the safety and efficacy of AlloNK®, an allogeneic cord blood-derived NK cell therapy, in combination with rituximab in relapsing forms of B-cell dependent rheumatologic diseases
Artiva Biotherapeutics Inc.15 个研究点 分布在 8 个国家目标入组 48 人开始时间: 2025年8月19日最近更新:
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 48
- 试验地点
- 15
- 主要终点
- Dose- limiting toxicities will be assessed at each dose level in a 3+3 design to determine the MTD and/or MAD. Disease specific primary efficacy endpoints will be measured at Week 52. 1. Idiopathic Inflammatory Myopathies: TIS ≥ 60 2. Systemic Sclerosis: rCRISS ≥ 50
研究概览
简要总结
To assess the safety and tolerability during the dose establishment of AlloNK® plus rituximab after lymphodepletion with cyclophosphamide and fludarabine in adult subjects with relapsing forms of B-cell dependent rheumatologic diseases.
To assess the preliminary efficacy of AlloNK® plus rituximab after lymphodepletion with cyclophosphamide and fludarabine in adult subjects with relapsing forms of B-cell dependent rheumatologic diseases.
研究设计
- 分配方式
- Not Applicable
- 主要目的
- A Phase 2a Open Label Study
- 盲法
- None
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 接受健康志愿者
- 否
入选标准
- •Male or female subjects ≥ 18 years of age.
- •Total Clinical European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (clinESSDAI) >
- •Salivary Flow Rate > 0.1 mL/min on stimulation
- •Evidence of Active IIM with subjects meeting at least two of the following criteria: a. MMT-8 score < 135/150 (indicating moderate-to-severe proximal muscle weakness) b. CK or aldolase level > 1.5 × ULN, consistent with active muscle injury. c. Physician Global Disease Activity ≥ 4/10 on a visual analog scale (VAS). d. CDASI Activity Score (for DM patients) ≥ 14, indicating moderate-to-severe skin activity. e. MRI finding evidence of muscle edema or inflammation on STIR or T2-weighted imaging f. ESR or CRP elevated, supportive of inflammatory activity (in context). g. Patient-reported symptoms of significant muscle fatigue or pain limiting daily activities (e.g., PROMIS-29 score ≥ 60).
- •Presence of extra-glandular domain involvement such as articular, renal, cutaneous, pulmonary, CNS, hematologic, lung, kidney and/or peripheral neuronal involvement.
- •Serological activity defined as hypocomplementemia or elevated CRP/ESR/IgG level, or cryoglobulins (excluding acute or chronic infection and other factors).
- •Patient failure to prior glucocorticoid therapy and at least two other immunosuppressive agents after 3 months of therapy, such as, but not limited to, cyclophosphamide, azathioprine, MMF, methotrexate, rituximab, or belimumab.
- •Women of childbearing potential and all male participants must agree to use a highly effective method of contraception for the duration of the trial or through at least 1 year after completing lymphodepleting chemotherapy dosing: Female contraceptive methods include: • Combined hormonal contraception with estrogen and progesterone to inhibit ovulation, including oral, intravaginal, and transdermal preparations • Progesterone-only hormonal contraception that inhibits ovulation, including oral, injectable, and implantable preparations • Intrauterine device • Intrauterine hormone-releasing system • Bilateral tubal ligation • Vasectomized partner (if the partner is the sole sexual partner of the female subject of childbearing potential participating in the study, and has undergone a successful vasoligation) • Complete abstinence from heterosexual intercourse Male contraceptive methods include: • Vasectomy • Complete abstinence from heterosexual intercourse • Barrier contraceptives in combination with female partner's hormonal or barrier method
- •Predicted diffusing capacity for carbon monoxide (DLCO) of ≥ 60% and a forced vital capacity (FVC) ≥ 70% at screening or within 3 months of screening with written documentation and report available.
- •Left ventricular ejection fraction (LVEF) ≥ 45% and no evidence of pericardial effusion as determined preferably by an echocardiogram (ECHO) or by multigated acquisition (MUGA) scan if ECHO is not available at screening or within 3 months of screening with written documentation and report available.
- •Screening laboratory values fulfilling the following requirements: a. Absolute Neutrophil Count (ANC) ≥ 1500/mm3 b. Platelets ≥ 100,000/mm3 c. Hemoglobin ≥ 8 g/dL d. Creatinine Clearance > 45 mL/minute as estimated by CKD-EPI equation (2021) e. Liver Transaminases (ALT, AST) ≤ 2x Upper Limit of Normal
- •For Subjects with Rheumatoid Arthritis (RA) Meet the 2010 ACR/EULAR classification criteria for RA
- •Performance status defined as ACR Functional Classification of Class III or less.
- •Clinical examination to rule out inflammatory foci in the body by the PI or by a relevant consultation per clinical indication.
- •For Subjects with Idiopathic Inflammatory Myopathies (IIMs) Meet 2017 EULAR/ACR classification crite for IIM, with a probability score meeting the threshold for “probable” or “definite” IIM.
- •Presence of at least one myositis-specific autoantibody (MSA). Acceptable MSAs include, but are not limited to, anti-Jo-1, anti-PL-7, anti-PL-12, anti-Mi-2, anti-SRP, anti-MDA5, anti-TIF1-γ, , and anti- SAE.
- •Refractory IIM is defined as an inadequate response or intolerance to at least 3 months of glucocorticoid therapy and at least two other immunosuppressive agents, such as (but not limited to) azathioprine, methotrexate, intravenous immunoglobulin (IVIG), mycophenolate mofetil (MMF), leflunomide, tacrolimus, cyclosporine, cyclophosphamide, and rituximab.
- •For dermatomyositis (DM) and polymyositis (PM) subjects only, cancer screening as follows: a. Age- and sex- appropriate cancer-screening (e.g., breast cancer, cervical cancer, colorectal cancer, lung cancer) within past 12 months as recommended by local or national guidelines b. Physical examination within the past 12 months to screen for evaluable malignancies (e.g., breast and pelvic examination for female patients, testicular and rectal examination for male patients, skin examination for malignancy-associated DM features)
- •For Subjects with Systemic Sclerosis (SSc) Meets the 2013 ACR/EULAR classification criteria for SSc (score ≥ 9).
- •Meet the following criteria for disease severity: • Skin: mRSS ≥ 15 AND • One or more of the following major organ involvements within previous 12 months: a) Lung: Interstitial lung disease with significant forced vital capacity (FVC) decline and/or diffusion capacity (DLCO) decline, pulmonary hypertension. b) GI tract: Dysphagia, significant gastroesophageal reflux, gastric paresis, gastric bleeding, intestinal dysmotility c) Heart: new or worsening cardiomyopathy, pericardial effusion, or arrhythmias. d) Renal: History of scleroderma renal crisis now stabilized (≥ 6 months from event).
- •Disease duration ≤ 3 years from first non-Raynaud’s symptom (to target immune-active phase).
- •Refractory SSc as defined by inadequate response or intolerance to at least two immunosuppressive agents for 3 months such as but not limited to, mycophenolate mofetil, cyclophosphamide, methotrexate, rituximab, tocilizumab, hydroxychloroquine, or azathioprine.
- •Rheumatoid Factor (RF) or Anti Citrullinated Protein Antibody (ACPA) positive.
- •Ability to understand the requirements of the study and provide written informed consent.
- •Willingness to comply with the study procedures.
- •High-sensitivity C-reactive protein (hs-CRP) > 3 mg/L or Erythrocyte Sedimentation Rate (ESR) > 28 mm/hr.
- •Subjects must have refractory rheumatoid arthritis, defined as: a. An inadequate response, loss of response, or intolerance to at least one conventional synthetic DMARD (csDMARD) (e.g., an inadequate response, loss of response, or intolerance at an approved dose after at least 3 months of treatment or for the duration as described in the approved label) AND b. An inadequate response, loss of response, or intolerance to at least two biologic or targeted synthetic DMARDs (b/tsDMARDs) with different mechanisms of action, such as a TNF inhibitor, abatacept, rituximab, tocilizumab, JAK inhibitor.
- •Minimum of 6 swollen joint counts (SJC) and 6 tender joint counts (TJC) of 66 swollen and 68 tender joint count evaluations.
- •Disease Activity Score 28 (DAS28-ESR) > 3.2 at screening.
- •For Subjects with Sjögren’s Disease (SjD) Meet 2016 ACR/EULAR criteria for Sjogren’s Disease with confirmatory diagnosis in the 24 weeks preceding the first day of the screening visit.
排除标准
- •For All Subjects Subjects who received cyclophosphamide within 28 days of Day
- •Study subjects with any of the following tuberculosis (TB) criteria: • Known active TB infection. • History of active TB infection involving any organ system or findings in other organ systems consistent with TB, unless adequately treated according to WHO/CDC therapeutic guidance and proven to be fully recovered upon consultation with a TB specialist. • Latent TB infection (LTBI) by QuantiFERON®-Gold Plus test unless appropriate prophylaxis is initiated at least 4 weeks prior to study medication dosing and will be continued to completion of prophylaxis. • High risk of acquiring TB infection, e.g., known close exposure to another person with active TB infection within 3 months prior to screening or significant time spent in a health care delivery setting or institution where individuals infected with TB are housed and where the risk of transmission is high within 3 months prior to Screening.
- •Currently pregnant or lactating.
- •Subjects who received the following agents in the relevant washout periods before screening: • Methotrexate within 4 weeks, except in patients with RA in whom methotrexate will be held from Day 1 until Week 4 and restarted on Week
- •Mycophenolate Mofetil (MMF) within 4 weeks • Azathioprine within 2 weeks • Leflunomide within 8 weeks or accelerated with cholestyramine • IVIG within 4 weeks • Hydroxychloroquine within 4 weeks • Additional washout requirements provided
- •Any medical, psychological, familial, or sociological condition that, in the opinion of the principal investigator, would impair the subject's ability to receive study treatment or comply with study requirements.
- •Subjects with a prior history of hypogammaglobulinemia or with low IgG levels (< 600 mg/dL).
- •Known hypersensitivity or contraindication to any drug products or any component of the drug products they plan to receive (e.g., cyclophosphamide, fludarabine, rituximab, AlloNK®).
- •History of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies or dimethyl sulfoxide (DMSO).
- •Prior treatment with any B-cell depleting therapy within 6 months of the start of the planned lymphodepletion regimen (e.g., rituximab, obinutuzumab, other depleting anti-CD20, anti-CD19 or anti-CD22 antibodies).
- •Prior treatment with any autologous or allogeneic cell therapy approach using genetically modified immune cells (e.g., T, NK, macrophages, or gamma-delta T-cells modified with chimeric antigen receptors [CAR]).
- •History of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant, or are due to receive such transplantation.
- •Any of the following suggestive of significant heart disease: • Moderate to severe congestive heart failure (New York Heart Association class III or IV), • Recent (within past 6 months) myocardial infarction, coronary stenting • Clinically relevant or significant electrocardiogram (ECG) abnormalities, including ECG with QT interval corrected for heart rate (QTc) > 500 msec.
- •Known past or current malignancy except for: • Cervical carcinoma of stage 1B or less, • Noninvasive basal cell or squamous cell skin carcinoma, • Noninvasive, superficial bladder cancer, • Prostate cancer with a current prostate specific antigen (PSA) level < 0.1 ng/mL • Any curable cancer with a complete response duration of > 2 years.
- •Have clinical evidence of significant unstable or uncontrolled acute or chronic diseases not due to IIMs, SSc, RA, or SjD which, in the opinion of the principal investigator, could confound the results of the study or put the subject at undue risk.
- •Subjects who received prednisone > 10 mg within 48 hours prior to Day
- •Have clinically significant central nervous system (CNS) involvement at screening (e.g., stroke, seizure, brain tumors, neurodegenerative conditions, or CNS infections) that, in the opinion of the investigator, would compromise the patient’s health, safety, or ability to participate in the trial.
- •Have a planned surgical procedure or a history of any other medical disease (e.g., cardiopulmonary), laboratory abnormality, or condition (e.g., poor venous access) that, in the opinion of the principal investigator, makes the subject unsuitable for the study.
- •Have any signs or symptoms of illness or infection that require systemic treatment, or any infection or infestation which, in the opinion of the investigator, would compromise the patient’s health, safety, or ability to participate in the trial.
- •Have received any vaccinations (live or inactivated) within 4 weeks of Day
- •Human immunodeficiency virus (HIV) infection, based on laboratory testing performed during the screening period.
- •Active Hepatitis C virus (HCV) infection, based on laboratory testing performed during screening period. • Anti-HCV antibody positivity will require reflex HCV RNA testing. HCV RNA positivity will be exclusionary.
- •Hepatitis B (HBV) infection • HBsAg positive • HBcAb positive will require reflex HBV DNA testing. HBV DNA positivity will be exclusionary.
结局指标
主要结局
Dose- limiting toxicities will be assessed at each dose level in a 3+3 design to determine the MTD and/or MAD. Disease specific primary efficacy endpoints will be measured at Week 52. 1. Idiopathic Inflammatory Myopathies: TIS ≥ 60 2. Systemic Sclerosis: rCRISS ≥ 50
Dose- limiting toxicities will be assessed at each dose level in a 3+3 design to determine the MTD and/or MAD. Disease specific primary efficacy endpoints will be measured at Week 52. 1. Idiopathic Inflammatory Myopathies: TIS ≥ 60 2. Systemic Sclerosis: rCRISS ≥ 50
3. Rheumatoid Arthritis: Disease Activity Score 28 (DAS28 - ESR) < 2.6 4. Sjögren’s Disease: Improvement from baseline in Clinical EULAR Sjögren's Syndrome Disease Activity Index (ClinESSDAI) of ≥ 4
3. Rheumatoid Arthritis: Disease Activity Score 28 (DAS28 - ESR) < 2.6 4. Sjögren’s Disease: Improvement from baseline in Clinical EULAR Sjögren's Syndrome Disease Activity Index (ClinESSDAI) of ≥ 4
次要结局
- 1. Safety will be assessed according to the SoA by monitoring AEs, co-meds, physical exams, ECGs, vital signs, and lab test findings. AEs will be coded using MedDRA and graded for severity by the Investigator using the Common Terminology Criteria for Adverse Events Version 5.0, with the exception of the following adverse events:
- 2. CRS events will be assessed by ASTCT grading; ICANS events will be assessed by ASTCT grading; GvHD diagnosis and grading of GvHD should follow the MAGIC criteria
- 3. The following biomarkers will be measured at baseline and at the timepoints specified in the SoA (Table 1): • Autoantibodies for RA: Rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA, e.g. anti-cyclic citrullinated peptide [CCP]). • Autoantibodies for IMM: anti-synthetase autoantibodies (e.g. anti-Jo-1, PL-7, PL-12, EJ, OJ, KS), anti-SRP, anti-Mi-2, anti-p140)
- 4. • Autoantibodies for SSc: e.g. anti-CENP-A/B/C, anti-topo-1, anti-RNAPI/III, anti-Scl70, anti-Jo1, anti-SSA. • Autoantibodies for SjD: Disease associated, e.g., anti-Ro (anti-SS-A) and anti-La (anti-SS-B)
- 6. Secondary Humoral Immunogenicity Endpoint Humoral immunogenicity will be determined by measuring anti-HLA antibodies specific to AlloNK® in subjects’ serum as specified in the SoA (Table 1). Exploratory objectives and associated endpoints are provided in the protocol.
研究者
Subhashis Banerjee
Scientific
Artiva Biotherapeutics Inc.
研究点 (15)
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