Cytokine Release Syndrome, ICANS
Conditions
Keywords
Methylene Blue, Cytokine Release Syndrome, Immune Effector Cell-Associated Neurotoxicity Syndrome, CAR-T Cell Therapy, Immunotherapy-Related Toxicity
Brief summary
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.
Detailed description
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.
Interventions
DRUGMethylene Blue
Intravenous infusion of methylene blue once daily for 3-5 consecutive days at doses of 1 mg/kg, 2 mg/kg, or 3 mg/kg, administered over 20 minutes, following CAR-T or bispecific antibody infusion in patients who develop Grade ≥1 CRS or ICANS.
Sponsors
Institute of Hematology & Blood Diseases Hospital, China
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosed with hematologic malignancies based on cytomorphology and immunophenotyping; age ≥18 years. 2. Received immunotherapy (e.g., CAR-T cells, bispecific antibodies) and developed CRS or ICANS of ASTCT Grade ≥1. 3. Estimated life expectancy ≥3 months. 4. Male and female participants of childbearing potential agree to use effective contraception. 5. Left ventricular ejection fraction (LVEF) \>45% by echocardiography. 6. Ability to understand and sign informed consent and willingness to comply with study requirements.
Exclusion criteria
1. Glucose-6-phosphate dehydrogenase (G6PD) deficiency. 2. Known allergy to methylene blue. 3. Pregnant or breastfeeding women. 4. Known HIV seropositivity. HIV testing may be required according to local laws or regulations. 5. 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). 6. Psychiatric disorders that may interfere with completion of treatment or informed consent. 7. Any other condition deemed unsuitable for participation by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Impact of Methylene Blue on CAR-T/T Cell Expansion in Peripheral Blood | 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. |
| Incidence and type of methylene blue-related serious adverse events (SAEs) | 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 Therapy Efficacy | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of corticosteroid use | Up to Day 35 after initiation of methylene blue treatment | Total duration (in days) of systemic corticosteroid administration for the management of CRS and/or ICANS after initiation of methylene blue treatment. |
| Proportion of Participants Requiring Vasopressors | Up to Day 35 after initiation of methylene blue treatment | Percentage of participants who required vasopressor therapy at any time after initiation of methylene blue treatment. |
| Duration of Vasopressor Therapy | Up to Day 35 after initiation of methylene blue treatment | Total number of days participants received vasopressor therapy after initiation of methylene blue treatment. |
| Incidence of Grade ≥3 CRS and ICANS | Up to Day 35 after initiation of methylene blue treatment | Proportion of participants who develop Grade 3 or higher cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS), assessed according to ASTCT 2019 grading criteria. |
| Duration of CRS and ICANS | Up to Day 35 after initiation of methylene blue treatment | The total duration (in days) of CRS and ICANS from onset until resolution to Grade 0, according to ASTCT 2019 criteria. |
Countries
China
Contacts
Primary ContactJianxiang Wang
Outcome results
None listed