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

Not Applicable

Recruiting

• Conditions: Cytokine Release Syndrome; ICANS
• Interventions: Drug: Methylene Blue

• Registration Number: NCT07169487
• Lead Sponsor: Institute of Hematology & Blood Diseases Hospital, China

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.

Study Timeline

• Study Start: 2025-06-28
• Study First Submitted: 2025-08-26
• Status Verified: 2025-09
• Study First Submitted QC: 2025-09-05
• Last Update Submitted: 2025-09-05
• Study First Posted: 2025-09-11
• Last Update Posted: 2025-09-11
• Primary Completion: 2028-06-28
• Study Completion: 2030-06-28

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 18

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Adjunctive Methylene Blue Dose-Escalation in Immunotherapy-related CRS and ICANS	Methylene Blue	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.

Primary Outcome Measures

Name	Time	Method
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 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.
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 Outcome Measures

Name	Time	Method
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.
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.

Trial Locations

Locations (1)

Institute of Hematology & Blood Diseases Hospital; 🇨🇳 Tianjin, Tianjin Municipality, China