Niacin CRT for Glioblastoma

Overseen by Gloria Roldan Urgoiti, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: AHS Cancer Control Alberta

Must be taking: Radiation, Temozolomide

Must not be taking: Statins

Disqualifiers: Other malignancies, Active liver disease, Unstable angina, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This study is evaluating whether a new drug called Niacin CRT™ can improve the survival of people with glioblastoma.

Will I have to stop taking my current medications?

The trial requires that patients stop taking HMG-COA reductase inhibitors (a type of cholesterol-lowering medication) at least 2 weeks before starting Niacin CRT™. For other medications, the protocol does not specify, so it's best to discuss with the trial team.

What data supports the effectiveness of the treatment Niacin CRT for glioblastoma?

Research shows that niacin (vitamin B3) can help the body's immune cells fight glioblastoma by reducing tumor size and improving survival in mice. Additionally, nicotinic acid, a form of niacin, has been found to reduce the invasion of glioma cells, which could help in treating this aggressive brain cancer. ^{1 2 3 4 5}

Is Niacin CRT safe for humans?

Niacin (Vitamin B3) has been studied for safety in various conditions. Some studies report side effects like nausea, vomiting, and liver issues when combined with other drugs. However, it is generally considered safe as it is a common vitamin used in many treatments. ^{1 4 6 7 8}

How does the drug Niacin CRT differ from other treatments for glioblastoma?

Niacin CRT is unique because it uses niacin (vitamin B3) to reactivate immune cells called macrophages and microglia, which can help fight glioblastoma by reducing tumor growth and improving survival. This approach is different from standard treatments as it focuses on boosting the body's immune response to the tumor. ^{1 2 3 4 9}

Research Team

Gloria Roldan Urgoiti, MD

Principal Investigator

Tom Baker Cancer Centre

Eligibility Criteria

This trial is for adults aged 18-75 with a new diagnosis of glioblastoma IDH wild type, who've had surgery to remove as much tumor as possible. They must be fit for standard cancer treatment and agree to use effective birth control. Excluded are those with certain health conditions like active heart disease, gout, liver disease, or prior treatments for glioblastoma.

Inclusion Criteria

Absence of any other serious medical condition according to the medical judgment of the Qualified Investigator prior to registration

My glioblastoma is IDH wild type.

Absence of known human immunodeficiency virus (HIV) infection, chronic hepatitis B or hepatitis C infection

Exclusion Criteria

Pregnant, breast-feeding, unable and/or unwilling to use contraception methods

Inability to provide informed consent

Individuals with MRI non-compatible metal in the body, or unable to undergo MRI procedures including allergy to gadolinium

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Niacin CRT™ dose will be escalated every 4 weeks until the maximum tolerated dose (MTD) is determined

Up to 24 weeks

Visits every 4 weeks for dose escalation

Concurrent Radiation and Temozolomide

Concurrent RT and TMZ for 6 weeks followed by 6-12 cycles of monthly TMZ

6 weeks

Weekly visits during radiation therapy

Maintenance Temozolomide

Monthly cycles of TMZ starting 28 days after the end of RT-TMZ, with dose adjustments based on tolerance

6-12 months

Monthly visits for chemotherapy cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Niacin CRT (Other)

Trial Overview The study tests the safety and maximum dose (Phase I) and effectiveness (Phase II) of Niacin CRT added to the Stupp protocol (standard radiation therapy plus Temozolomide chemotherapy), in treating newly diagnosed glioblastoma without IDH mutation.

Participant Groups

Group I: Niacin Experimental Treatment 1 Intervention

Niacin controlled release technology (CRT): Niacin CRT™ is to be started 7 days before concurrent Radiation Therapy (RT)- Temozolomide (TMZ) treatment. Chemo/Radiation Therapy: For all patients, regardless of the phase of the study, concurrent RT and TMZ for 6 weeks followed by 6-12 cycles of monthly TMZ will be given. Concurrent Temozolomide: TMZ will be administered from the first to the last day of RT at 75 mg/m2 orally (PO) for a maximum of 49 days. Monthly Temozolomide: Cycles of chemotherapy Day 1 to Day 5 every 28 days will start 28 days (+/- 2 days) after the end of RT-TMZ. First cycle of TMZ is administered at 150 mg/m2 Day 1-Day 5 by mouth (PO) and increased to 200 mg/m2 Day 1-Day 5 PO from cycle 2 onwards if well tolerated. While 6 cycles are standard of care, the Neuro-Oncologist may continue up to 12 cycles if clinically appropriate.

Who Is Running the Clinical Trial?

AHS Cancer Control Alberta

Lead Sponsor

Trials

188

Recruited

26,900+

Tom Baker Cancer Centre

Collaborator

Trials

30

Recruited

8,900+

Findings from Research

Niacin (vitamin B3) has been identified as a potential treatment for glioblastomas by reactivating monocytes and macrophages, which can help reduce the growth of brain tumor-initiating cells (BTICs).

In mouse models, niacin treatment not only increased the presence of immune cells in tumors and reduced tumor size but also prolonged survival, especially when combined with the chemotherapy drug temozolomide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Control of brain tumor growth by reactivating myeloid cells with niacin. Sarkar, S., Yang, R., Mirzaei, R., et al.[2021]

Pyridoxine (vitamin B6) supplementation significantly decreases the viability of human glioblastoma cells (U-87 MG) in a dose- and time-dependent manner, likely by promoting apoptosis through increased active caspase 3 expression.

Cobalamin (vitamin B12) does not have the same cytotoxic effect as pyridoxine and can inhibit the cytotoxicity of pyridoxine when both are combined, suggesting a complex interaction that may influence treatment strategies for glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of pyridoxine or cobalamin supplementation on apoptosis and cell cycle progression in a human glioblastoma cell line. Martínez-Mendiola, CA., Estrada, JA., Zapi-Colín, LÁ., et al.[2023]

Epidemiological studies indicate that higher prediagnosis levels of Vitamin D are linked to a lower risk of glioblastoma multiforme (GBM), and supplemental Vitamin D may reduce mortality in GBM patients, suggesting its potential efficacy as a therapeutic agent.

The combination of Calcitriol (a form of Vitamin D), All-Trans Retinoic Acid (ATRA), and Temozolomide may enhance treatment outcomes for high-grade glial tumors, while adding acetazolamide could mitigate risks associated with Vitamin D and A excess, highlighting a potential safer treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From epidemiology and neurometabolism to treatment: Vitamin D in pathogenesis of glioblastoma Multiforme (GBM) and a proposal for Vitamin D + all-trans retinoic acid + Temozolomide combination in treatment of GBM. Elmaci, I., Ozpinar, A., Ozpinar, A., et al.[2020]

Nicotinic acid (NA) has been shown to effectively inhibit the invasion of malignant glioma cells both in laboratory settings and in a rat model, suggesting its potential as a therapeutic option.

The mechanism of action involves upregulating E-cadherin, which enhances cell adhesion and reduces the invasive properties of glioma cells by promoting the degradation of the repressive transcription factor Snail1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinic acid inhibits glioma invasion by facilitating Snail1 degradation. Li, J., Qu, J., Shi, Y., et al.[2018]

A new treatment approach for glioblastoma multiforme combining accelerated radiotherapy with Nicotinamide and Carbogen was found to be feasible and safe, with no significant side effects from the radiotherapy schedule itself.

Patients with complete surgical removal of the tumor who received the full treatment regimen showed a promising median survival of 35 months, suggesting potential benefits of this combined therapy compared to conventional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carbogen and nicotinamide combined with unconventional radiotherapy in glioblastoma multiforme: a new modality treatment. Fatigante, L., Ducci, F., Cartei, F., et al.[2019]

Extended-release niacin/laropiprant (ERN/LRPT) demonstrated a favorable safety profile, with fewer flushing-related side effects compared to traditional niacin (ERN-NSP), based on data from 4747 participants across multiple studies lasting up to 52 weeks.

While there were slight increases in liver enzymes with ERN/LRPT, these were reversible and not linked to liver damage, indicating that ERN/LRPT can be safely used to enhance the lipid-modifying effects of niacin without significant adverse effects on muscle or liver health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of extended-release niacin/laropiprant in patients with dyslipidemia. McKenney, J., Bays, H., Koren, M., et al.[2015]

In a study involving 19 glioblastoma patients treated with nicotinamide, carbogen, and radiotherapy, 8 patients experienced significant side effects leading to protocol discontinuation, highlighting potential safety concerns.

The treatment regimen was associated with increased early radiation neurotoxicity, suggesting that while exploring new therapies, careful monitoring for adverse effects is crucial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerance of nicotinamide and carbogen with radiation therapy for glioblastoma. Pickles, T., Graham, P., Syndikus, I., et al.[2019]

In a study of 82 dyslipidemic patients treated with niacin, 83% tolerated the treatment well, achieving beneficial effects on high-density lipoprotein cholesterol (HDL-C) levels, indicating niacin's efficacy as a lipid-modifying drug.

However, sustained-release niacin was associated with a higher risk of hepatitis, particularly in patients with diabetes, suggesting that its use should be closely monitored, and its availability as a nonprescription drug should be reconsidered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niacin revisited: clinical observations on an important but underutilized drug. Henkin, Y., Oberman, A., Hurst, DC., et al.[2019]

Lipid-soluble vitamins, particularly A, D, and E, have shown potential in modulating biomarkers related to glioblastoma (GBM) pathophysiology, with 40 differentially expressed biomarkers identified from 19 studies.

Retinoids from vitamin A promote cell differentiation and inhibit stemness in GBM cells, while vitamin D affects cell cycle biomarkers, and vitamin E derivatives influence apoptosis, suggesting these vitamins could be explored as alternative therapeutic strategies for GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers Regulated by Lipid-Soluble Vitamins in Glioblastoma. Osman, DE., Phon, BWS., Kamarudin, MNA., et al.[2022]

References

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

Control of brain tumor growth by reactivating myeloid cells with niacin. [2021]

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

Effect of pyridoxine or cobalamin supplementation on apoptosis and cell cycle progression in a human glioblastoma cell line. [2023]

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

From epidemiology and neurometabolism to treatment: Vitamin D in pathogenesis of glioblastoma Multiforme (GBM) and a proposal for Vitamin D + all-trans retinoic acid + Temozolomide combination in treatment of GBM. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Nicotinic acid inhibits glioma invasion by facilitating Snail1 degradation. [2018]

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

Carbogen and nicotinamide combined with unconventional radiotherapy in glioblastoma multiforme: a new modality treatment. [2019]

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

Safety of extended-release niacin/laropiprant in patients with dyslipidemia. [2015]

7. Ireland pubmed.ncbi.nlm.nih.gov

Tolerance of nicotinamide and carbogen with radiation therapy for glioblastoma. [2019]

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

Niacin revisited: clinical observations on an important but underutilized drug. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Biomarkers Regulated by Lipid-Soluble Vitamins in Glioblastoma. [2022]