Adjunctive Methylene Blue for Immunotherapy-related CRS and ICANS: Phase I Study

Institute of Hematology & Blood Diseases Hospital, China

Status and phase: Enrolling; Phase 1

Conditions: Cytokine Release Syndrome; ICANS

Treatments: Drug: Methylene Blue

Study type: Interventional

Funder types: Other

Identifiers

NCT07169487

IIT2025072

Details and patient eligibility

About

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.

Full 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.

Enrollment: 18 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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18 participants in 1 patient group

Adjunctive Methylene Blue Dose-Escalation in Immunotherapy-related CRS and ICANS

Experimental group

Description:

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.

Treatment:

Drug: Methylene Blue