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

Official title

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

Overview

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

• Drug Methylene 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.

Primary outcome measures

• Incidence and type of methylene blue-related serious adverse events (SAEs) [Time frame: Up to Day 35 after initiation of methylene blue treatment]
• Impact of Methylene Blue on CAR-T/T Cell Expansion in Peripheral Blood [Time frame: Up to Day 35 after initiation of methylene blue treatment]
• Impact of Methylene Blue on CAR-T/T Cell Therapy Efficacy [Time frame: Baseline to Day 35 post-treatment initiation]

Secondary outcome measures (5)

• Incidence of Grade ≥3 CRS and ICANS [Time frame: Up to Day 35 after initiation of methylene blue treatment]
• Duration of CRS and ICANS [Time frame: Up to Day 35 after initiation of methylene blue treatment]
• Duration of corticosteroid use [Time frame: Up to Day 35 after initiation of methylene blue treatment]
• Proportion of Participants Requiring Vasopressors [Time frame: Up to Day 35 after initiation of methylene blue treatment]
• Duration of Vasopressor Therapy [Time frame: Up to Day 35 after initiation of methylene blue treatment]

Eligibility criteria

Inclusion criteria

• 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 ≥1.
• 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.

Exclusion criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Institute of Hematology & Blood Diseases Hospital — Tianjin

Identifiers

NCT: NCT07169487 · IIT2025072

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗