Evaluation of Haploidentical, Donor-Derived B Lymphocyte Infusions in Patients With Amyotrophic Lateral Sclerosis
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Infusion associated adverse events of special interest
研究概览
简要总结
This study is testing whether giving people with ALS specially matched immune cells called B cells from a related donor is safe. Up to 10 participants will each receive two B cell infusions at least 60 days apart. The main goals are to watch closely for side effects, see whether the participant's immune system rejects the donor cells, and determine whether this treatment should be studied further in people with ALS. The first three participants will receive the infusions in the hospital with extra safety spacing between participants; if those infusions appear safe, the remaining participants may receive them in an outpatient setting.
详细描述
This is a phase 1, non-randomized, open-label study to assess the safety and pharmacokinetics of up to 2 doses of donor B cells. Up to 10 recipients will each receive 2 infusions of donor B cells at doses of ≥ 2.0 x 10^8 and ≤ 1.0 x 10^9 donor B cells delivered at least 60 days apart. The first three participants will receive infusions as inpatients in a staggered fashion 30 days apart. After completion of a 30-day observation of the third participant after the second infusion, study investigators will determine whether the infusions are safe and well-tolerated and that there are no indications of significant immune rejection of the donor B cells. In such a case the remaining participants will receive 2 infusions in an outpatient setting with no mandatory staggering interval. Each participant will be followed for six months after the second infusion.
Donors. Each subject will be consented along with a relative meeting the HLA matching requirements to serve as a donor. The patient and potential donor will be HLA (A, B and DR- B1) tested and the potential donor will be a haploidentical match to the recipient, will have cleared all medical and infectious diseases screening tests, and will have agreed to be the B cell donor for this study. Each donor will undergo one or more leukapheresis procedures each yielding up to 1.5 mL of a concentrated white cell fraction. Purified B cells will be derived from these cells for a target final yield of between 2.0 x 108 and 1.0 x 109 B cells. Purified donor B cells will be stored in liquid nitrogen and thawed at bedside for infusion into participant.
Recipients. Prior to infusion, each enrolled subject will have a pre-infusion visit (study Day -50 to -40) where medical history will be taken, vitals and ALS-related measurements will be taken and a blood sample drawn to establish baseline blood counts, chemistry, and immunologic profile.
Treatment. All participants will receive up to 2 infusions of ≥ 2.0 x 10^8 and ≤ 1.0 x 10^9 donor B cells with the second infusion no less than 60 days after the first infusion. Participants will receive infusions with no preparatory treatment. Donor B cells in a concentration of 1.0 x 10^7 donor B cells/mL in a volume of up to 100 mL will be delivered over a 2-hour period through a peripheral line pre-incubated with a 4% solution of human serum albumin.
Evaluation. The first three participants will receive infusions as inpatients to carefully monitor responses to infusions for up to 24 hours. These participants will be staggered 30 days apart. If infusions of inpatient participants appear to be well tolerated and safe, the remaining participants will receive infusions as outpatients with no staggering.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed diagnosis of ALS that meets the revised El Escorial criteria for probable lab-supported, probable, or definite ALS.
- •Age 18-70 years.
- •Vital capacity of >65%.
- •ALSFRS-R score of >
- •Absence of clinically important abnormalities on screening labs, including but not limited to ALT/AST < 3x ULN, Bilirubin <1.5x ULN (unless there is documented history of Gilbert's disease), serum Cr < 1.5x ULN, WBC > 3.5, HCT >33, Plts >
- •Negative tests for HIV, HepB sAg, HCV.
- •Available potential donor who must be a haploidentical match to the recipient and agree to be the B cell donor for this study.
- •Note: Participants are eligible if they are taking any, all, or none of the following: riluzole, edaravone, and/or high-dose methylcobalamine; and the start date of these medications are at least 30 days prior to the baseline visit.
排除标准
- •Unable or unwilling to comply with protocol requirements.
- •Known current or history of recurrent bacterial, viral, fungal, mycobacterial, or other opportunistic infection.
- •Use of tofersen (Qalsody).
- •Use of Rituximab (Rituxan), Ocrelizumab (Ocrevus), Ofatumumab (Kesimpta, Arzerra), Epratuzumab (LymphoCide), Belimumab (Benlysta), MEDI-551, or other anti-CD20, anti-CD19, or anti-CD22 antibodies.
- •Use of Atacicpet or other BlyS or APRIL inhibitors.
- •Use of Chimeric antigen-receptor T cells targeting CD19 or CD20, including tisagenlecleucel (Kymriah), Aaxicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), and lisocabtagene maraleucel (Breyanzi).
- •Additional active neurological disease that could confound the participant's ALS symptoms.
- •Major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening.
- •Immunization with live-attenuated vaccines within 4 weeks of screening. Study participant must agree to forgo live-attenuated vaccines throughout the study.
- •Chronic immunosuppression (any chronic immunosuppressive immunotherapy including daily oral steroid use > 6 months).
- •Other active autoimmune disease except psoriasis or hypothyroidism.
- •Active malignancy (excluding skin cancer other than melanoma) within 5 years.
- •History of any of the following: cardiac insufficiency (defined as New York Heart Association III/IV), unstable ischemic heart disease, uncontrolled cardiac arrhythmias, or uncontrolled hypertension (defined as systolic blood pressure >170 mmHg or diastolic blood pressure >110 mmHg).
- •Unstable cardiac, renal, hepatic, endocrine, pulmonary or hematologic disease, at the discretion of the PI.
- •Anything that, in the opinion of the PI, would place the participant at increased risk or preclude the participant's full compliance with or the completion of the study.
- •Participant unwilling to practice contraception for the duration of the study. Men and women of childbearing potential (WOCBP) should use an approved method of birth control and agree to continue to use this method for the duration of the study.
- •Acceptable methods of contraception include abstinence, female participants/partner's use of hormonal contraceptive (oral, implanted, or injected) in conjunction with a barrier method (WOCBP only) (e.g., diaphragm, cervical cap, male condom, and female condom and spermicidal foam, sponges, and film), female participant's/partner's use of an intrauterine device (IUD), or if the female participant/partner is surgically sterile (e.g., bilateral tubal ligation, hysterectomy) or two years postmenopausal at time of screening. All male participants/partners (excluding men who have been sterilized) must agree to consistently and correctly use a condom for duration of the study. In addition, participants may not donate sperm for the duration of the study.
- •Participation in another interventional trial or use of an experimental ALS product with an ongoing clinical development program in an expanded access program, compassionate use program or through practitioner prescription. Over the counter medications are acceptable, as are standard of care ALS medications.
研究组 & 干预措施
ALS patients receiving infusions of haploidentical donor B cells
ALS patients receiving infusions of haploidentical donor B cells between 200 million and 1 billion cells per infusion with the second infusion 60 days after the first.
干预措施: B cell infusion (Biological)
结局指标
主要结局
Infusion associated adverse events of special interest
时间窗: Up to 6 months after 2nd infusion
Safety and tolerability of up to 2 infusions of donor B cells at individual doses of between 2.0 x 10\^8 and 1.0 x 10\^9 donor B cells defined by: * Incidence of all AEs, as defined for the 30-day time point, at 60 days. * Incidence of Treatment Emergent Serious Adverse Events (TE-SAEs) at 30 days defined as the composite of graft-versus-host disease, other persistent immunologic abnormalities, bleeding disorders, stroke, myocardial infarction, or death.
Evidence of host rejection of infused cells
时间窗: Within 4 weeks of 2nd infusion
Donor cell rejection: Indications of immune rejection of B cell infusions defined by changes in specific blood markers and ex vivo cell assays after either the first or second infusion of donor B cells compared to baseline levels of each.
次要结局
未报告次要终点
研究者
Mark Poznansky
Professor of Medicine; Director Vaccine & Immunotherapy Center
Massachusetts General Hospital