Dexamethasone + Simvastatin for Neurotoxicity After Lymphoma Treatment

Overseen By Cancer Center Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Masonic Cancer Center, University of Minnesota

Must be taking: Simvastatin

Must not be taking: Statins

Disqualifiers: CNS lymphoma, GVHD, Hepatitis, HIV, others

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

Compensation: Varies

Number of Visits: 1

Duration: 30 days

37 Participants Needed

Trial Summary

What is the purpose of this trial?

Open-label, single-arm, single center pilot study to assess safety and feasibility of administering dexamethasone intrathecally and simvastatin orally during axicabtagene ciloleucel (axi-cel) treatment. Feasibility will be measured by the proportion of patients completing two-thirds (2/3) of their assigned treatments. The study will be deemed feasible if 2/3 or more of the patients complete 2/3 or more of their allocated treatments.

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 already on a statin drug for high cholesterol, you must be willing to switch to 40 mg/day of simvastatin.

What data supports the effectiveness of the drug Dexamethasone + Simvastatin for neurotoxicity after lymphoma treatment?

Research shows that simvastatin, when combined with dexamethasone, can enhance the effectiveness of chemotherapy in treating myeloma and lymphoma cells. This suggests that the combination might help in managing neurotoxicity after lymphoma treatment by potentially improving the overall treatment response. ^{1 2 3 4 5}

Is the combination of Dexamethasone and Simvastatin safe for humans?

Dexamethasone is commonly used in treatments and has been associated with some concerns about toxicity, particularly in children with leukemia, where it may affect quality of life and behavior. However, no specific safety data for the combination of Dexamethasone and Simvastatin was found in the provided research articles. ^{2 6 7 8 9}

How does the drug Dexamethasone + Simvastatin differ from other treatments for neurotoxicity after lymphoma treatment?

Dexamethasone + Simvastatin is unique because it combines a steroid (dexamethasone) known for reducing inflammation and a cholesterol-lowering drug (simvastatin) that may have protective effects on the nervous system. This combination aims to address neurotoxicity, a serious side effect of lymphoma treatment, by potentially reducing inflammation and protecting nerve cells, which is different from standard treatments that may not target these specific mechanisms. ^{2 6 10 11 12}

Research Team

Joseph Maakaron, MD

Principal Investigator

Masonic Cancer Center, University of Minnesota

Eligibility Criteria

Adults aged 18-80 with certain types of lymphoma (like DLBCL) who haven't responded to at least two chemotherapy treatments can join. They must be able to have lumbar punctures, not be pregnant or breastfeeding, use contraception, and have stable major organ function. Those already on statins or with uncontrolled infections, heart issues, bleeding risks that can't be managed, active HIV/hepatitis B/C or CNS lymphoma cannot participate.

Inclusion Criteria

My kidneys, liver, and heart are functioning well enough for treatment.

My cancer did not respond to 2+ chemotherapy treatments or returned after stem cell transplant.

My lymphoma is one of the specified types (DLBCL, primary mediastinal, high grade, or from follicular lymphoma).

Exclusion Criteria

I have not had a recent heart attack or unstable chest pain.

I am not pregnant or breastfeeding and have a negative pregnancy test.

I have an active HIV infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Treatment

Simvastatin 40 mg/day is started at least 5 days prior to apheresis

1 week

1 visit (in-person)

Treatment

Participants receive axicabtagene ciloleucel (Axi-Cel) treatment with intrathecal dexamethasone and oral simvastatin

30 days

Multiple visits for drug administration and sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Dexamethasone
• Simvastatin

Trial Overview This study tests the safety and practicality of giving dexamethasone directly into the spinal fluid and simvastatin orally to patients undergoing axi-cel therapy for lymphoma. Success is if most patients complete most of their treatment without serious problems.

Participant Groups

Group I: Simvastatin and Dexamethasone Experimental Treatment 2 Interventions

Simvastatin 40 mg/day will be started at least 5 days prior to apheresis and will be continued until day +30 after infusion. Intrathecal dexamethasone 8 mg will be administered on days (related to CAR-T infusion) -1, +6, +13, (+/- 2 days).

Who Is Running the Clinical Trial?

Masonic Cancer Center, University of Minnesota

Lead Sponsor

Trials

285

Recruited

15,700+

Findings from Research

Dexamethasone (Dex) significantly reduces the sensitivity of C6 glioma cells to methotrexate (MTX), allowing more cells to survive even at high concentrations of MTX.

This protective effect of Dex was also observed in human TE671 cells, indicating that the interaction between Dex and MTX is not limited to a specific species.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone induced partial resistance to methotrexate in C6-glioma cells. Wolff, JE., Jürgens, H.[2013]

In a study involving 45 children with acute lymphoblastic leukemia (ALL), both dexamethasone and prednisone showed similar improvements in health-related quality of life (HRQOL) and behavior over one year, suggesting that dexamethasone does not negatively impact these outcomes compared to prednisone.

Despite concerns about the potential neuropsychological toxicity of dexamethasone, the results indicate that its use in ALL treatment is associated with significant improvements in HRQOL without significant differences in outcomes compared to traditional therapy with prednisone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HRQOL implications of treatment with dexamethasone for children with acute lymphoblastic leukemia (ALL). Eiser, C., Davies, H., Jenney, M., et al.[2016]

In a study of 18 patients with primary central nervous system lymphoma (PCNSL), the combination of high-dose methotrexate (MTX) and CHOD chemotherapy resulted in complete responses in 11 patients and partial responses in 3, with a median survival of 25.5 months.

Despite showing some activity against PCNSL, the pre-irradiation MCHOD regimen did not demonstrate superior efficacy compared to MTX alone and was associated with higher toxicity, including significant myelotoxicity and other serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD). Glass, J., Shustik, C., Hochberg, FH., et al.[2019]

In the EURO-LB02 trial involving 319 patients with lymphoblastic lymphoma, the 5-year event-free survival rate was 82%, but the previously reported 90% rate for T-cell lymphoblastic lymphoma was not achieved, primarily due to increased toxic deaths and central nervous system relapses.

Patients receiving dexamethasone during induction experienced significantly more severe toxicities compared to those on prednisone, leading to treatment delays, although dexamethasone may be more effective in preventing central nervous system relapses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma. Landmann, E., Burkhardt, B., Zimmermann, M., et al.[2018]

References

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

A Randomized Controlled Open-Label Pilot Study of Simvastatin Addition to Whole-Brain Radiation Therapy in Patients With Brain Metastases. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Outcomes of high‑dose methotrexate for CNS prophylaxis in diffuse large B‑cell lymphoma with an intermediate or high CNS‑International Prognostic Index: A single‑center retrospective cohort study. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of high-dose simvastatin in refractory and relapsed chronic lymphocytic leukemia patients. [2019]

4. Italy pubmed.ncbi.nlm.nih.gov

Dose-finding study of high-dose simvastatin combined with standard chemotherapy in patients with relapsed or refractory myeloma or lymphoma. [2013]

5. England pubmed.ncbi.nlm.nih.gov

Co-administration of simvastatin and cytotoxic drugs is advantageous in myeloma cell lines. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Methotrexate encephalopathy: Two cases in adult cancer patients, who recovered with pathophysiologically based therapy. [2020]

7. Greece pubmed.ncbi.nlm.nih.gov

Dexamethasone induced partial resistance to methotrexate in C6-glioma cells. [2013]

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

Successful non-neurotoxic therapy (without radiation) of a multifocal primary brain lymphoma with a methotrexate, vincristine, and BCNU protocol (DEMOB). [2019]

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

HRQOL implications of treatment with dexamethasone for children with acute lymphoblastic leukemia (ALL). [2016]

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

Therapy of primary central nervous system lymphoma with pre-irradiation methotrexate, cyclophosphamide, doxorubicin, vincristine, and dexamethasone (MCHOD). [2019]

11. Italy pubmed.ncbi.nlm.nih.gov

Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma. [2018]

12. England pubmed.ncbi.nlm.nih.gov

EEG with extreme delta brush in young female with methotrexate neurotoxicity supports NMDA receptor involvement. [2018]