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

22 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination Cytarabine, Methotrexate, and Hydrocortisone for treating Cassava Neurotoxicity Syndrome?

The combination of Methotrexate, Hydrocortisone, and Cytarabine has been used effectively in treating meningeal leukemia, achieving complete central nervous system remission in nearly all patients. Although neurotoxicity is a concern, it is often transient and manageable, allowing for the continuation of treatment. ^{1 2 3 4 5}

Is the combination of Cytarabine, Methotrexate, and Hydrocortisone generally safe for humans?

Methotrexate, one of the drugs in the combination, can cause side effects like liver problems, skin reactions, and neurotoxicity (nerve damage) at high doses. However, these side effects are often related to the dose and can be managed with careful monitoring and treatment adjustments. ^{4 6 7 8 9}

How is the drug Cytarabine + Methotrexate + Hydrocortisone unique for treating Cassava Neurotoxicity Syndrome?

This treatment is unique because it combines cytarabine and methotrexate, which are known to cause neurotoxicity, with hydrocortisone, a corticosteroid that can help resolve such neurotoxic effects. The use of hydrocortisone may help mitigate the neurotoxic side effects of the other drugs, offering a novel approach to managing symptoms. ^{2 4 10 11 12}

What is the purpose of this trial?

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.

Research Team

Stephen E Spurgeon

Principal Investigator

OHSU Knight Cancer Institute

Eligibility Criteria

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

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

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Case of neuromyelitis optica: bilateral sensorineural hearing loss and transverse myelopathy following intrathecal chemotherapy. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Managing therapy-associated neurotoxicity in children with ALL. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Combination intrathecal therapy for meningeal leukemia: two versus three drugs. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Clinico-radiological profile, management and follow-up of methotrexate induced neurotoxicity in children with acute lymphoblastic leukemia. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Neurotoxicity associated with systemic high-dose cytosine arabinoside. [2017]

6. Italy pubmed.ncbi.nlm.nih.gov

Low dose treatment with methotrexate-adverse drug reactions survey. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Ethnic-specific predictors of neurotoxicity among patients with pediatric acute lymphoblastic leukemia after high-dose methotrexate. [2023]

8. India pubmed.ncbi.nlm.nih.gov

Methotrexate-Induced Toxic Epidermal Necrolysis: A Rare Case Report and Review of Literature. [2020]

9. Japan pubmed.ncbi.nlm.nih.gov

[Evaluation of severe side effects of high-dose methotrexate in osteosarcoma]. [2013]

10. United States pubmed.ncbi.nlm.nih.gov

Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy--a Pediatric Oncology Group study. [2017]

11. United States pubmed.ncbi.nlm.nih.gov

A Case of Subacute Encephalopathy Developing After Treatment With Clofarabine and Methotrexate That Resolved With Corticosteroids. [2018]

12. Spain pubmed.ncbi.nlm.nih.gov

[Neurotoxicity due to methotrexate in paediatric patients. Description of the clinical symptoms and neuroimaging findings]. [2013]