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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether dexamethasone (a corticosteroid) and simvastatin (a cholesterol-lowering medication) can reduce nerve-related side effects for individuals undergoing a specific lymphoma treatment called axi-cel. The goal is to determine the safety and feasibility of using these medications during treatment. This trial suits individuals with certain types of lymphoma who have not responded well to prior chemotherapy and have no active brain-related lymphoma issues. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

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.

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

Research has shown that combining simvastatin and dexamethasone is safe and generally well-tolerated. Early results suggest this combination might reduce nerve-related side effects in patients undergoing CAR-T cell therapy, a type of cancer treatment. No major safety concerns have emerged with this combination so far. However, further information is needed to fully understand its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using dexamethasone and simvastatin for treating neurotoxicity after lymphoma treatment because this combination targets inflammation and cholesterol pathways in a novel way. Most current treatments focus on general symptom management, but simvastatin, a cholesterol-lowering medication, is thought to protect nerve cells from damage. Dexamethasone, an anti-inflammatory steroid, is delivered directly into the spinal fluid, potentially reducing inflammation more effectively in the nervous system. This approach could lead to quicker and more targeted relief from neurotoxicity symptoms compared to traditional treatments.

What evidence suggests that dexamethasone and simvastatin might be effective for neurotoxicity after lymphoma treatment?

Research has shown that simvastatin and dexamethasone might help with nerve damage after lymphoma treatment. In this trial, participants will receive a combination of these two drugs. One study found that simvastatin can induce cancer cell death in conditions like lymphoma. Another study discovered that dexamethasone might reduce nerve damage by helping the body clear certain drugs faster. This suggests that using both simvastatin and dexamethasone together could protect the brain from nerve damage during cancer treatments. While early results are still being collected, this combination shows promise for reducing this specific side effect. ^{3 6 7 8 9}

Who Is on the Research Team?

Joseph Maakaron, MD

Principal Investigator

Masonic Cancer Center, University of Minnesota

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/16585018/

Dose-finding study of high-dose simvastatin combined with ... The most frequently reported side-effects were fatigue, gastrointestinal CTC grade 1-2 and neutropenic fever. The dose-limiting toxicity was neutropenic sepsis ...

2. trialx.com trialx.com/clinical-trials/listings/264406/neurotoxicity-prophylaxis-with-intrathecal-dexamethasone-and-simvastatin-post-axi-cel/

Neurotoxicity Prophylaxis With Intrathecal Dexamethasone ... This trial gathers preliminary information on the potential effect of the combination of dexamethasone and simvastatin on treating Neurotoxicity ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10672071/

Drug–Drug Interactions Involving Dexamethasone in ... Dexamethasone also decreased misonidazole neurotoxicity in mice by significantly increasing drug clearance and shortening drug half-life, ...

4. researchgate.net researchgate.net/publication/7195059_Dose-finding_study_of_high-dose_simvastatin_combined_with_standard_chemotherapy_in_patients_with_relapsed_or_refractory_myeloma_or_lymphoma

Dose-finding study of high-dose simvastatin combined with ... We recently described that simvastatin effectively induced apoptosis in myeloma and lymphoma tumor cells by inhibition of ...

5. lifeextension.com lifeextension.com/protocols/cancer/repurposing-common-drugs-as-adjuvant-cancer-therapies?srsltid=AfmBOoo9SdDhcljEeSgvTsikhc22GrqfAzUtQpW__81P0wEKL5f39khX

Drug Repurposing in Cancer A meta-analysis of 14 studies with a combined total of 33,137 pancreatic cancer patients found statin use was associated with a lower mortality rate in those ...

6. withpower.com withpower.com/trial/early-phase-1-neurotoxicity-syndromes-7-2020-6de09

Dexamethasone + Simvastatin for Neurotoxicity After Lymphoma ... However, no specific safety data for the combination of Dexamethasone and Simvastatin was found in the provided research articles. Show more. How ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123100954

Simvastatin with Intrathecal Dexamethasone Reduces ... We are currently evaluating the safety and feasibility of administering simvastatin in addition to intrathecal dexamethasone to decrease the incidence and/or ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12048402/

Neurological complications associated with chimeric antigen ... Unexpected neurologic complications following a novel lymphoma treatment 'expected' to give rise to neurologic toxicity. BMJ Case Rep 2019 ...

9. researchgate.net researchgate.net/publication/376166852_Simvastatin_with_Intrathecal_Dexamethasone_Reduces_Neurotoxicity_in_Adults_Receiving_Chimeric_Antigen_Receptor_CAR_T-Cells_Treatment

Simvastatin with Intrathecal Dexamethasone Reduces ... Conclusions Preliminary results show that simvastatin and intrathecal dexamethasone appear to be feasible, safe, and effective in reducing the incidence and ...