Intrathecal Cytarabine, Methotrexate, and Hydrocortisone for the Prevention of High-Grade Chimeric Antigen Receptor T-Cell-Associated Neurotoxicity Syndrome

A Phase 2 Study of Prophylactic IT Chemotherapy to Prevent High-Grade Chimeric Antigen Receptor (CAR) T-Cell-Associated Neurotoxicity Syndrome

This phase II trial tests how well cytarabine (Ara-C), methotrexate, and hydrocortisone given between the spinal cord and the membranes that protect it (intrathecal [IT]) works in preventing high-grade immune effector-associated neurotoxicity syndrome (ICANS) in patients receiving chimeric antigen receptor (CAR) T-cell therapy. ICANS is a challenging complication of CAR T-cell therapy that causes neurological effects varying from mild headaches or temporary confusion to hallucinations, swelling in the brain, and seizures. Between 20%-70% of patients receiving CAR T-cell therapy show symptoms of neurotoxicity.

Study Overview

• Status: Recruiting
• Conditions: Hematopoietic and Lymphatic System Neoplasm
• Intervention / Treatment: Procedure: Lumbar Puncture; Drug: Methotrexate; Drug: Therapeutic Hydrocortisone; Drug: Cytarabine; Procedure: Biospecimen Collection

Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate the efficacy of IT chemotherapy in the prevention of high grade ICANS.

SECONDARY OBJECTIVES:

I. To evaluate the efficacy of IT chemotherapy in the prevention of any grade ICANS.

II. To evaluate safety of IT chemotherapy. III. To evaluate the effect of IT chemotherapy on corticosteroid use. IV. To evaluate the effect of IT chemotherapy on anakinra use.

EXPLORATORY OBJECTIVES:

I. To evaluate the effect of IT chemotherapy on time to ICANS onset. II. To evaluate the effect of IT chemotherapy on duration of ICANS. III. To evaluate the burden of treatment mediated serious adverse events (SAEs).

OUTLINE:

Patients receive cytarabine IT, methotrexate IT, and hydrocortisone IT over 3-5 minutes via lumbar puncture (LP) on day 4 post-standard of care (SOC) Axi-cel (Yescarta) or Brexu-cel (Tecartus) in the absence of unacceptable toxicity or development of ICANS. Patients who do not develop ICANS of any grade, also receive hydrocortisone IT on day 7 post SOC CAR T-cell therapy. Additionally, patients undergo cerebrospinal fluid (CSF) sample collection throughout the study.

After completion of study treatment, patients are followed for up to 30 days.

• Study Type: Interventional
• Enrollment (Estimated): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239
      • Recruiting
      • OHSU Knight Cancer Institute
      • Principal Investigator: Stephen E. Spurgeon
      • Contact: Stephen E. Spurgeon; Phone Number: 503-494-8950; Email: spurgeos@ohsu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent. Participant or legally authorized representative (LAR) must provide written informed consent prior to any study-specific procedures or interventions
• Age ≥ 18 years. All genders, races, and ethnic groups will be included
• Must be receiving SOC Yescarta® or Tecartus® in the inpatient setting

• Agree to adhere to institutional guidelines for contraception during the first 30 days post CAR-T

  • Rationale for eligibility criteria based on contraception and pregnancy (both participants and partners of a sperm-producing participant): It shall be known to all participants that the effects of CAR-T or IT chemotherapy on the developing human fetus are unknown. For this reason, persons of reproductive potential must agree to use adequate contraception. Should a participant or participant's sexual partner become pregnant or suspect a pregnancy while participating in this study, the individual should inform their treating physician immediately
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Platelet count > 50,000/mm^3 (μL)
• Adequate coagulation tests including international normalized ratio (INR) < 1.6 and fibrinogen > 100

Exclusion Criteria:

• Active/concurrent diagnosis of any central nervous system (CNS) hematologic malignancy

  • History or presence of CNS disorder such as poorly controlled seizure disorder (seizure within the 12 months), transverse myelitis, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement
• Known history of hypersensitivity to IT chemotherapy

• Subject has a contraindication to LP including:

  • Presence of a posterior fossa mass
  • Skin infection near puncture site
  • Uncorrected bleeding diathesis
  • Suspicion of increased intracranial pressure
  • Acute spinal cord trauma
• Subject is receiving an antiplatelet and/or anticoagulant that cannot be held prior to LP according to best available evidence
• Known bleeding disorders
• Any other significant medical illness, abnormality, or condition that would, in the Investigator's judgement, make the participant inappropriate for study participation or would put the participant at risk

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Supportive Care (cytarabine, methotrexate, hydrocortisone); Patients receive cytarabine IT, methotrexate IT, and hydrocortisone IT over 3-5 minutes via LP on day 4 post-SOC CAR T-cell therapy in the absence of unacceptable toxicity or development of ICANS. Patients who do not develop ICANS of any grade, also receive hydrocortisone IT on day 7 post SOC CAR T-cell therapy. Additionally, patients undergo CSF sample collection throughout the study.

Procedure: Lumbar Puncture; Undergo lumbar puncture; Other Names: LP; Spinal Tap; Drug: Methotrexate; Given IT; Other Names: Abitrexate; Folex; Mexate; MTX; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate-AQ; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; Jylamvo; Drug: Therapeutic Hydrocortisone; Given IT; Other Names: Aeroseb-HC; Barseb HC; Barseb-HC; Cetacort; Cort-Dome; Cortef; Cortenema; Cortifan; Cortisol; Cortispray; Cortril; Dermacort; Domolene; Eldecort; Hautosone; Heb-Cort; Hydrocortisone; Hydrocortone; Hytone; Komed-HC; Nutracort; Proctocort; Rectoid; Drug: Cytarabine; Given IT; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453; Procedure: Biospecimen Collection; Undergo CSF sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of American Society for Transplantation and Cellular Therapy (ASTCT) ≥ grade 3 immune-effector cell associated neurotoxicity syndrome (ICANS)	Will be reported using the efficacy set. Point estimate, along with exact two-sided 95% confidence interval will be reported.	From first dose of intrathecal (IT) chemotherapy (chimeric antigen receptor [CAR]-T day 4) to CAR-T day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of ASTCT any grade ICANS	Will be reported using the efficacy set. Point estimate, along with exact two-sided 95% confidence interval will be reported.	From first dose of IT chemotherapy (CAR-T day 4) to CAR-T day 30
Incidence of lumbar puncture/IT treatment related adverse events (AEs) and serious adverse events (SAEs)	Will be reported using the safety set. AEs will be tabulated by the Medical Dictionary for Regulatory Activities version (v) 21.1. preferred term and system organ class and a preferred term. The severity of the AE will be assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version (CTCAE) v 5.0. Descriptive statistics using the safety evaluable population, will be used to report on all on-study AEs, grade 3-4 AEs, treatment-related AEs, grade 3-4 treatment-related AEs, SAEs, treatment-related SAEs, and AEs leading to discontinuation per CTCAE v 5.0. Grade 3-4 laboratory abnormalities will be summarized using worst grade NCI CTCAE v 5.0 criteria.	From first dose of IT chemotherapy (CAR-T day 4) to CAR-T day 30
Mean (range) cumulative dose of corticosteroid use	Will be reported using the efficacy set. The cumulative dose will be calculated as the sum of all corticosteroid administered over the study period, expressed in milligrams (mg) of prednisone-equivalent.	From first dose of IT chemotherapy (CAR-T day 4) to CAR-T day 30
Incidence of anakinra use	Will be reported using the efficacy set. Point estimate, along with exact two-sided 95% confidence interval will be reported.	From first dose of IT chemotherapy (CAR-T day 4) to CAR-T day 30

Collaborators and Investigators

• Sponsor: OHSU Knight Cancer Institute
• Collaborators: Oregon Health and Science University; American Society of Clinical Oncology
• Investigators: Principal Investigator: Stephen E Spurgeon, OHSU Knight Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): June 4, 2025
• Primary Completion (Estimated): April 30, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: March 19, 2025
• First Submitted That Met QC Criteria: March 19, 2025
• First Posted (Actual): March 26, 2025

Study Record Updates

• Last Update Posted (Actual): January 30, 2026
• Last Update Submitted That Met QC Criteria: January 28, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Chemically-Induced Disorders; Poisoning; Neurotoxicity Syndromes; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Nucleic Acids, Nucleotides, and Nucleosides; Biopsy; Polycyclic Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Pregnanes; Steroids; Fused-Ring Compounds; Nucleosides; Pterins; Pteridines; Arabinonucleosides; Aminopterin; Pregnenediones; Pregnenes; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; 17-Hydroxycorticosteroids; Diagnostic Techniques, Neurological; Methotrexate; Cytarabine; Hydrocortisone; Specimen Handling; Spinal Puncture; merphos
• Other Study ID Numbers: STUDY00028106 (Other Identifier: OHSU Knight Cancer Institute); NCI-2025-00937 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No