Cytarabine + Methotrexate + Hydrocortisone for Cassava Neurotoxicity Syndrome

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: OHSU Knight Cancer Institute

Must not be taking: Antiplatelets, Anticoagulants

Disqualifiers: CNS malignancy, Seizure disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate how effectively a combination of three drugs—cytarabine, methotrexate, and hydrocortisone—can prevent ICANS, a potential side effect of CAR T-cell therapy. ICANS can range from headaches to severe issues like confusion, brain swelling, or seizures. The trial targets individuals receiving CAR T-cell therapy, specifically those using Yescarta® or Tecartus®, who do not have active brain-related illnesses or bleeding disorders. Participants will receive the drug combination directly into the space around their spinal cord. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are on antiplatelet or anticoagulant medications, you may need to hold them before certain procedures. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using cytarabine, methotrexate, and hydrocortisone together can yield mixed safety results, particularly when administered intrathecally (directly into the spinal area). Methotrexate, for instance, has been linked to serious side effects in the brain and nervous system, such as severe neurological symptoms. Some patients have experienced these issues after receiving methotrexate in this manner, as demonstrated in a case where a patient developed changing neurological symptoms post-treatment.

While methotrexate can be effective, this study indicated that nerve-related side effects can occur. In some instances, these side effects are severe and long-lasting. However, methotrexate has also been shown to help prevent relapses in the central nervous system when used correctly.

Cytarabine and hydrocortisone are also components of this treatment. Cytarabine, a type of chemotherapy drug, can cause side effects when used in the spinal area. It is crucial to carefully weigh the benefits and risks.

In summary, evidence about the safety of this combination is mixed. Those considering participation in a trial should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of cytarabine, methotrexate, and hydrocortisone for Cassava Neurotoxicity Syndrome because this mix offers a potentially new way to tackle the condition by using intrathecal (IT) delivery directly into the cerebrospinal fluid. This method allows the drugs to reach the central nervous system more effectively, which is crucial for treating neurotoxicity. Unlike traditional treatments that might not penetrate the blood-brain barrier efficiently, this approach ensures that the active ingredients target the affected area more directly, potentially leading to faster and more effective results. This is especially promising for patients who develop neurotoxicity following treatments like Axi-cel (Yescarta) or Brexu-cel (Tecartus).

What evidence suggests that this treatment might be an effective treatment for neurotoxicity?

Research has shown that a combination of three drugs—cytarabine, methotrexate, and hydrocortisone—can help treat neurotoxicity syndrome. In this trial, participants will receive these drugs as part of the supportive care arm. For some patients, injecting these drugs into the spine improved symptoms like alertness and awareness. One study found that this treatment quickly helped severe cases of ICANS. Another report showed that patients experienced fast improvements in their neurological symptoms with this drug combination. These findings provide promising evidence that this treatment could help manage ICANS in patients receiving CAR T-cell therapy. ^{1 3 6 7 8}

Who Is on the Research Team?

Stephen E Spurgeon

Principal Investigator

OHSU Knight Cancer Institute

Are You a Good Fit for This Trial?

This trial is for cancer patients receiving CAR T-cell therapy who are at risk of developing a serious side effect called ICANS, which affects the brain and nerves. Participants must meet certain health standards to be eligible.

Inclusion Criteria

Platelet count must be greater than 50,000/mm^3 (μL)

Adequate coagulation tests including international normalized ratio (INR) must be less than 1.6 and fibrinogen must be greater than 100

Written informed consent must be provided by participant or legally authorized representative (LAR) prior to any study-specific procedures or interventions

Exclusion Criteria

Known history of hypersensitivity to IT chemotherapy

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

I have a blood cancer affecting my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cytarabine IT, methotrexate IT, and hydrocortisone IT via lumbar puncture on days 1 and 5 post-standard of care CAR T-cell therapy

1 week

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including CSF sample collection

4 weeks

Ongoing monitoring

What Are the Treatments Tested in This Trial?

Interventions

• Cytarabine
• Hydrocortisone
• Methotrexate

Trial Overview The study tests if giving cytarabine, methotrexate, and hydrocortisone directly into the spinal fluid can prevent ICANS in patients undergoing CAR T-cell therapy. It's a phase II trial to see how effective this preventive treatment is.

How Is the Trial Designed?

Group I: Supportive Care (cytarabine, methotrexate, hydrocortisone) Experimental Treatment 5 Interventions

Patients receive cytarabine IT, methotrexate IT, and hydrocortisone IT over 3-5 minutes via LP on days 1 and 5 post-SOC Axi-cel (Yescarta) or Brexu-cel (Tecartus) in the absence of unacceptable toxicity or development of ICANS. Additionally, patients undergo CSF sample collection throughout the study.

Who Is Running the Clinical Trial?

OHSU Knight Cancer Institute

Lead Sponsor

Trials

239

Recruited

2,089,000+

Oregon Health and Science University

Collaborator

Trials

1,024

Recruited

7,420,000+

American Society of Clinical Oncology

Collaborator

Trials

40

Recruited

148,000+

Published Research Related to This Trial

In a study of 94 patients with rheumatoid arthritis and psoriatic arthritis, 17% experienced adverse drug reactions (ADRs) from low-dose methotrexate (MTX), with the most common being leucopenia, thrombocytopenia, and gastrointestinal issues.

The primary concern with long-term low-dose MTX therapy is hepatotoxicity, which can lead to painful and costly diagnosis and treatment, prompting changes or discontinuation of therapy in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose treatment with methotrexate-adverse drug reactions survey. Getov, I., Dimitrova, Z., Petkova, V.[2013]

In a study involving 91 children with meningeal leukemia, both two-agent (methotrexate and hydrocortisone) and three-agent (adding cytosine arabinoside) intrathecal chemotherapy regimens achieved high rates of complete CNS remission (100% and 96%, respectively).

While the three-agent therapy resulted in a longer median CNS remission duration (64.6 weeks) compared to the two-agent therapy (47.2 weeks), the difference was not statistically significant, and both regimens showed reduced toxicity compared to methotrexate alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination intrathecal therapy for meningeal leukemia: two versus three drugs. Sullivan, MP., Moon, TE., Trueworthy, R., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06895473

Intrathecal Cytarabine, Methotrexate, and Hydrocortisone ... This phase II trial tests how well cytarabine (Ara-C), methotrexate, and hydrocortisone given between the spinal cord and the membranes that protect it ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11099209/

Case report: Rapid resolution of grade IV ICANS after first line ... Solh M.M. et al. reported a clinical study that explored the safety and efficacy of IT administration of methotrexate and/or cytarabine for the ...

3. ar.iiarjournals.org ar.iiarjournals.org/content/42/8/3853

Intrathecal Chemotherapy as a Potential Treatment for ... IT chemotherapy with 12 mg methotrexate and 50 mg hydrocortisone resulted in prompt neurological improvement in both patients. One of them passed away due to ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2025-00937

Intrathecal Cytarabine, Methotrexate, and Hydrocortisone ... This phase II trial tests how well cytarabine (Ara-C), methotrexate, and hydrocortisone given between the spinal cord and the membranes that protect it ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7252557/

Intrathecal chemotherapy for management of steroid-refractory ... On day 22, the patient's neurologic symptoms improved, with dramatic recovery of alertness, verbalization, and orientation. Subsequently, his ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12269288/

Methotrexate-induced neurotoxicity: Diagnostic challenges ... We report an 18-year-old ALL patient who developed severe, fluctuating neurological symptoms 11 days after the third intrathecal administration ...

7. haematologica.org haematologica.org/article/view/haematol.2020.268565

Methotrexate-related central neurotoxicity: clinical ... Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX ...

8. clinicsinoncology.com clinicsinoncology.com/full-text/cio-v3-id1392.php

Progressive Neurotoxicity after Intrathecal Methotrexate ... We describe the gradually progressive, treatment-refractory, fatal neurotoxicity from combined intrathecal chemotherapy with methotrexate and cytarabine in a ...