Exploration of Efficacy and Safety of Adjunctive Methylene Blue in the Treatment of Immunotherapy-related CRS and ICANS: A Prospective, Single-arm, Phase I Clinical Study
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Incidence and type of methylene blue-related serious adverse events (SAEs)
研究概览
简要总结
This Phase I, prospective, single-arm clinical study aims to evaluate the efficacy and safety of adjunctive methylene blue (MB) in patients experiencing cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) following CAR-T cell therapy or bispecific antibody treatment. Preclinical studies demonstrated that MB alleviates CRS/ICANS-related symptoms, preserves the antitumor function of T cells, and modulates neuroinflammation without compromising immune efficacy. The study will employ a 3+3 dose-escalation design with three MB dosing cohorts, with treatment administered intravenously for 3-5 consecutive days. Vital signs, laboratory markers, and neurological status will be closely monitored, and concomitant standard supportive therapies will be permitted.
详细描述
Methylene blue (MB), originally approved for methemoglobinemia, has demonstrated hemodynamic and neuroprotective effects. Preclinical data indicate that MB alleviates CRS/ICANS symptoms, protects blood-brain barrier integrity, limits microglial overactivation, and preserves T-cell antitumor function.
This Phase I, prospective, single-arm clinical trial will investigate MB as an adjunctive therapy for immunotherapy-related CRS and ICANS. Eligible patients are those receiving CAR-T cells or bispecific antibodies who subsequently develop Grade ≥1 CRS or ICANS, as defined by ASTCT 2019 criteria. Participants will be enrolled in a 3+3 dose-escalation schema with the following cohorts:
Cohort 1: 1 mg/kg once daily, intravenous infusion over 20 minutes Cohort 2: 2 mg/kg once daily, intravenous infusion over 20 minutes Cohort 3: 3 mg/kg once daily, intravenous infusion over 20 minutes Treatment will be administered for 3-5 consecutive days. Patients will undergo continuous assessment of vital signs (temperature, blood pressure, oxygen saturation), laboratory biomarkers (CRP, ferritin, cytokines), and neurotoxicity grading throughout therapy. Dosing adjustments will be based on real-time safety and efficacy evaluations.
Concomitant standard-of-care supportive interventions will be allowed, including tocilizumab (maximum of two doses), dexamethasone, ruxolitinib, cetuximab, and other symptomatic treatments. This trial seeks to establish the safety profile and preliminary efficacy of MB in mitigating immune therapy-related toxicities, potentially offering a novel strategy to improve the tolerability and safety of CAR-T and bispecific antibody therapies.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosed with hematologic malignancies based on cytomorphology and immunophenotyping; age ≥18 years.
- •Received immunotherapy (e.g., CAR-T cells, bispecific antibodies) and developed CRS or ICANS of ASTCT Grade ≥
- •Estimated life expectancy ≥3 months.
- •Male and female participants of childbearing potential agree to use effective contraception.
- •Left ventricular ejection fraction (LVEF) >45% by echocardiography.
- •Ability to understand and sign informed consent and willingness to comply with study requirements.
排除标准
- •Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
- •Known allergy to methylene blue.
- •Pregnant or breastfeeding women.
- •Known HIV seropositivity. HIV testing may be required according to local laws or regulations.
- •History of clinically significant ventricular arrhythmia, unexplained syncope (not vasovagal), sinoatrial block, or higher-degree atrioventricular (AV) block with chronic bradycardia (unless a permanent pacemaker is implanted).
- •Psychiatric disorders that may interfere with completion of treatment or informed consent.
- •Any other condition deemed unsuitable for participation by the investigator.
研究组 & 干预措施
Adjunctive Methylene Blue Dose-Escalation in Immunotherapy-related CRS and ICANS
To evaluate the efficacy and safety of adjunctive methylene blue in the treatment of immunotherapy-related cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in patients receiving CAR-T or bispecific antibody therapy, using a 3+3 dose-escalation Phase I design.
干预措施: Methylene Blue (Drug)
结局指标
主要结局
Incidence and type of methylene blue-related serious adverse events (SAEs)
时间窗: Up to Day 35 after initiation of methylene blue treatment
The proportion of participants who experience methylene blue-related serious adverse events (SAEs), categorized by type, assessed according to NCI CTCAE v5.0 criteria. SAEs will be judged by the investigator to be related to methylene blue administration.
Impact of Methylene Blue on CAR-T/T Cell Expansion in Peripheral Blood
时间窗: Up to Day 35 after initiation of methylene blue treatment
Evaluation of CAR-T or T cell expansion in peripheral blood following methylene blue treatment, assessed by flow cytometry.
Impact of Methylene Blue on CAR-T/T Cell Therapy Efficacy
时间窗: Baseline to Day 35 post-treatment initiation
Proportion of participants achieving complete remission (CR), partial remission (PR), stable disease (SD), or experiencing relapse/progression, assessed according to immunotherapy response criteria (see Study Protocol for full criteria).
次要结局
- Incidence of Grade ≥3 CRS and ICANS(Up to Day 35 after initiation of methylene blue treatment)
- Duration of CRS and ICANS(Up to Day 35 after initiation of methylene blue treatment)
- Duration of corticosteroid use(Up to Day 35 after initiation of methylene blue treatment)
- Proportion of Participants Requiring Vasopressors(Up to Day 35 after initiation of methylene blue treatment)
- Duration of Vasopressor Therapy(Up to Day 35 after initiation of methylene blue treatment)