Ferumoxytol + Vitamin C for Glioblastoma

(XACT-Fe-GBM-01 Trial)

Overseen By Bryan G. Allen, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Bryan Allen

Must be taking: Temozolomide

Must not be taking: Warfarin, Antiretrovirals

Disqualifiers: Insulin requirement, Pregnancy, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding ferumoxytol (an iron-based drug) and vitamin C to the usual treatment helps fight glioblastoma, a type of brain cancer. Participants will receive these additions along with standard treatments like radiation and the chemotherapy drug temozolomide. The trial aims to determine if this new combination is safe and potentially more effective. It seeks individuals recently diagnosed with glioblastoma who are about to start their first round of treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I have to stop taking my current medications?

The trial requires stopping certain medications. You cannot participate if you are currently using warfarin, flecainide, methadone, amphetamines, quinidine, chlorpropamide, or antiretroviral drugs and cannot switch or stop them. If you need insulin or iron supplements, you also cannot participate. Over-the-counter iron supplements are okay.

Will I have to stop taking my current medications?

The trial requires you to stop taking certain medications, such as warfarin, flecainide, methadone, amphetamines, quinidine, chlorpropamide, and antiretroviral drugs, unless a substitution is possible. If you are on these medications and cannot switch, you may not be eligible to participate.

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

Research has shown that ferumoxytol, a type of iron particle, is FDA-approved for treating iron deficiency anemia, indicating general safety for humans. However, its use with high-dose vitamin C remains under study. Some studies have examined the effectiveness of this combination with temozolomide, a chemotherapy drug, and radiation therapy.

Research has also explored the safety of using ferumoxytol and vitamin C together, focusing on optimal dosing and potential side effects. So far, no major issues have emerged, but it's important to note that this is still in the early stages of testing, so not all possible side effects are known.

Participants should remember that this trial is in its early phase. While safety is being studied, the treatment is not yet confirmed to be safe for everyone. Always consult a healthcare provider to understand the potential risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ferumoxytol and vitamin C for glioblastoma because it introduces a novel approach to treating this aggressive brain cancer. Unlike standard treatments that typically rely on chemotherapy and radiation alone, this investigational treatment uses ferumoxytol, an iron supplement, to enhance the effects of radiation therapy. Additionally, high-dose vitamin C is administered intravenously, which may boost the body's ability to fight cancer cells. This combination could potentially improve the effectiveness of existing treatments, offering new hope for better outcomes in glioblastoma patients.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

Research shows that adding temozolomide to radiation therapy can significantly improve survival rates for glioblastoma patients. Studies have found that this combination increases the ten-year survival rate from 47% to 70% and extends the average survival time compared to radiation alone.

In this trial, participants in Cohort 1 and Cohort 2 will receive ferumoxytol and vitamin C alongside their treatment. Research on these additions is still in the early stages. The hypothesis is that ferumoxytol might make tumor cells more sensitive to high doses of vitamin C, potentially enhancing treatment effectiveness. However, specific data on its effectiveness for glioblastoma is not yet available. ^{1 2 3 4 6}

Who Is on the Research Team?

John M. Buatti, MD

Principal Investigator

University of Iowa

Are You a Good Fit for This Trial?

Adults over 18 with newly diagnosed glioblastoma or diffuse midline glioma, able to start treatment within 6 weeks of surgery and take oral medication. Participants must be medically fit for standard therapy, not pregnant or breastfeeding, without significant other CNS diseases or conditions like hemochromatosis, G6PD deficiency, uncontrolled illnesses, certain drug dependencies (e.g., warfarin), and no prior overlapping radiation treatments.

Inclusion Criteria

My doctor says I am healthy enough for specific cancer treatments.

Agree to use of highly effective contraception from screening until at least 90 days after the last study treatment (study participant should not discontinue contraception until discussing with their treating oncologist(s))

Agree to Lifestyle Considerations throughout study duration

Exclusion Criteria

I have had radiation treatment in the same area before.

History of Steven's Johnson Syndrome

I have G6PD deficiency.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation Phase

Participants receive radiation therapy combined with temozolomide, ferumoxytol, and ascorbate

6-8 weeks

Daily visits for radiation, multiple IV infusions

Adjuvant Phase

Participants receive cycles of temozolomide and ascorbate, with initial ferumoxytol infusion

Up to 6 cycles (28 days each)

Regular visits for chemotherapy cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks post-radiation

Regular follow-up visits

Long-term Follow-up

Participants are monitored for progression-free survival and overall survival

Up to 60 months for PFS, up to 20 years for OS

What Are the Treatments Tested in This Trial?

Interventions

• External Beam Radiation Therapy
• Ferumoxytol Injection
• Pharmacological Ascorbate
• Temozolomide

Trial Overview The trial is testing the addition of ferumoxytol (an iron supplement) and high-dose vitamin C to the usual chemoradiation treatment for brain tumors. All participants will receive these additional treatments alongside standard care with temozolomide chemotherapy and external beam radiation therapy.

How Is the Trial Designed?

Group I: Cohort 2 Experimental Treatment 4 Interventions

Radiation Phase * Ascorbate: 87.5 g administered intravenously (IV) three times each calendar week for approximately 8 weeks. * Ferumoxytol: 512 g administered intravenously (IV) the day before radiation, about 1 week after dose 1, during weeks 5 to 6 of radiation therapy, and then a week after that (for a total of 4 ferumoxytol infusions). * Radiation: 61.2 Gray (given 1.8 Gray once daily, 5 days per week, for about 7 weeks) or 60 Gray (2.0 Gray once daily for 5 days per week for about 6 weeks) * Temozolomide: 75 mg/m2, taken orally, once daily, every day, for up to 49 days or until radiation is completed (whichever comes first). Adjuvant Phase * Temozolomide: 150 to 200 mg/m2, taken orally, once daily, for five days out of 28 days (where 28 days is one cycle of chemotherapy) for up to six cycles * Ascorbate: 87.5 g administered intravenously (IV) twice each calendar week of the cycle * Ferumoxytol: 512 g administered intravenously (IV) the first day of the first cycle of

Group II: Cohort 1 (starting) Experimental Treatment 4 Interventions

Radiation Phase * Ascorbate: 87.5 g administered intravenously (IV) three times each calendar week for approximately 8 weeks. * Ferumoxytol: 512 g administered intravenously (IV) the day before radiation and then during weeks 5 to 6 of radiation therapy. * Radiation: 61.2 Gray (given 1.8 Gray once daily, 5 days per week, for about 7 weeks) or 60 Gray (2.0 Gray once daily for 5 days per week for about 6 weeks) * Temozolomide: 75 mg/m2, taken orally, once daily, every day, for up to 49 days or until radiation is completed (whichever comes first). Adjuvant Phase * Temozolomide: 150 to 200 mg/m2, taken orally, once daily, for five days out of 28 days (where 28 days is one cycle of chemotherapy) for up to six cycles * Ascorbate: 87.5 g administered intravenously (IV) twice each calendar week of the cycle * Ferumoxytol: 512 g administered intravenously (IV) the first day of the first cycle of chemotherapy.

External Beam Radiation Therapy is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in United States as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in Canada as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in Japan as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in China as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in Switzerland as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Who Is Running the Clinical Trial?

Bryan Allen

Lead Sponsor

Trials

4

Recruited

130+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Holden Comprehensive Cancer Center

Collaborator

Trials

27

Recruited

710+

Published Research Related to This Trial

The combination drug menadione/ascorbate (M/A) effectively suppressed glioblastoma tumor growth and increased survival in mice without the adverse side effects commonly associated with the standard treatment, temozolomide (TMZ).

M/A demonstrated selective cytotoxicity by inducing oxidative stress specifically in glioblastoma cells while sparing normal microglial cells, suggesting it could be a safer adjunct therapy for glioblastoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological Strategy for Selective Targeting of Glioblastoma by Redox-active Combination Drug - Comparison With the Chemotherapeutic Standard-of-care Temozolomide. Sumiyoshi, A., Shibata, S., Zhelev, Z., et al.[2021]

In a randomized trial involving 144 patients with anaplastic astrocytoma (AA) and glioblastoma (GBM), neoadjuvant temozolomide (NeoTMZ) did not show a survival advantage for the overall population or for GBM patients compared to radiotherapy alone.

However, patients with AA who received NeoTMZ had a significantly longer median survival of 95.1 months compared to 35.2 months for those receiving only radiotherapy, indicating a potential benefit of NeoTMZ specifically for AA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial. Malmström, A., Poulsen, HS., Grønberg, BH., et al.[2018]

In a study of 103 glioblastoma patients treated with standard temozolomide and radiotherapy, the median overall survival was found to be 13.7 months, highlighting the effectiveness of this treatment regimen.

Three key prognostic factors were identified that negatively impacted overall survival: age over 65 years, a Medical Research Council (MRC) scale score of 3-4, and the occurrence of postoperative complications, suggesting that these factors can help predict patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Age, Neurological Status MRC Scale, and Postoperative Morbidity are Prognostic Factors in Patients with Glioblastoma Treated by Chemoradiotherapy. Verlut, C., Mouillet, G., Magnin, E., et al.[2020]

Melatonin and alpha-lipoic acid (LA) showed significant potential in reducing the proliferation of glioblastoma cells when used in combination with the chemotherapy drug temozolomide (TMZ), with LA demonstrating the most promise.

The study suggests that these antioxidants may enhance the effectiveness of TMZ by decreasing reactive oxygen species, indicating a possible synergistic effect in treating glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Do Anti-Oxidants Vitamin D3, Melatonin, and Alpha-Lipoic Acid Have Synergistic Effects with Temozolomide on Cultured Glioblastoma Cells? McConnell, DD., McGreevy, JW., Williams, MN., et al.[2023]

In a study of 1157 glioblastoma multiforme patients, the addition of temozolomide (TMZ) to radiotherapy (RT) significantly improved median overall survival from 9.0 months with RT alone to 16.2 months with RT + TMZ (P < .001).

The two-year survival rate increased from 4% with RT alone to 25% with the combination of RT and TMZ, confirming the efficacy of TMZ in enhancing survival outcomes in GBM patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A population-based study on the effect of temozolomide in the treatment of glioblastoma multiforme. Rønning, PA., Helseth, E., Meling, TR., et al.[2022]

In a study of 79 patients with glioblastoma, the combination of radiotherapy and temozolomide resulted in a median overall survival of 18.3 months and 2-year survival rate of 37.1%, which aligns with previous international studies.

The main side effect observed was hematologic toxicity in 8.8% of patients, indicating that while the treatment is effective, monitoring for blood-related side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcome of concomitant chemoradiotherapy followed by adjuvant temozolomide therapy for glioblastaomas: single-center experience. Jeon, HJ., Kong, DS., Park, KB., et al.[2018]

In a study of 67 patients with newly diagnosed glioblastoma multiforme, the combination of temozolomide, thalidomide, and radiation therapy resulted in a median survival of 73 weeks, indicating a favorable outcome compared to those not receiving adjuvant chemotherapy.

The treatment was generally well tolerated, but the specific benefit of adding thalidomide to temozolomide remains uncertain, as the survival outcomes were similar to those seen with other chemotherapy regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. Chang, SM., Lamborn, KR., Malec, M., et al.[2018]

In a phase II clinical trial involving 21 patients with newly diagnosed glioblastoma multiforme (GBM), the combination of temozolomide (TMZ) with radiotherapy resulted in a one-year survival rate of 58% and a median survival time of 15.7 months, indicating its efficacy in extending survival.

The treatment regimen was well-tolerated, with only mild to moderate non-hematological side effects and minimal severe hematological toxicity, suggesting that TMZ has a favorable safety profile compared to traditional chemotherapy agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. Lanzetta, G., Campanella, C., Rozzi, A., et al.[2018]

The study confirmed that the generic temozolomide capsules (TOZ039) are bioequivalent to the brand Temodal® capsules, with pharmacokinetic parameters falling within the acceptable range for both 20-mg and 100-mg doses in 29 patients with brain tumors.

The treatment was found to be safe, with no treatment-related severe adverse events or mortality reported, although 82.8% of patients experienced some adverse effects, highlighting the importance of monitoring patient responses during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal&#174;) in glioma patients in China. Hu, C., Lin, Q., Liu, C., et al.[2021]

In a study of 87 newly diagnosed glioblastoma patients, only 5% experienced severe myelotoxicity during treatment with temozolomide (TMZ) and radiation therapy, indicating that while the risk exists, it is relatively low.

Factors such as female sex, low pretreatment platelet counts, and specific genetic markers were identified as potential predictors of severe myelotoxicity, suggesting that personalized treatment approaches could help mitigate risks in vulnerable patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study. Lombardi, G., Rumiato, E., Bertorelle, R., et al.[2018]

Temozolomide (TMZ) is generally safe with mild to moderate side effects, but this case report highlights a rare instance of severe aplastic anemia (AA) in a 68-year-old female patient following treatment for glioblastoma, indicating a potential serious risk associated with the drug.

The patient's AA was managed successfully with supportive care, including platelet transfusions and growth factor treatment, and her blood counts returned to normal within 38 days, emphasizing the importance of monitoring blood parameters during and after TMZ treatment to detect such rare toxicities early.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. Gilbar, PJ., Pokharel, K., Mangos, HM.[2022]

Ferumoxytol (FMX), an FDA-approved iron treatment, can enhance the effectiveness of pharmacological ascorbate in killing glioblastoma (GBM) cells by catalyzing the release of ferrous iron (Fe2+) and increasing hydrogen peroxide (H2O2) levels, which selectively targets cancer cells over normal cells.

In animal models, the combination of FMX, pharmacological ascorbate, and chemoradiation significantly improved tumor control in GBM xenografts that were previously unresponsive to ascorbate therapy, suggesting a promising new treatment strategy for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Magnetite nanoparticles as a kinetically favorable source of iron to enhance GBM response to chemoradiosensitization with pharmacological ascorbate. Petronek, MS., Teferi, N., Caster, JM., et al.[2023]

In a retrospective study of 62 patients with anaplastic glioma, the combination of temozolomide (TMZ) and radiation therapy (RT) did not show a significant improvement in progression-free survival compared to RT alone, with median times of 14.8 months for TMZ-RT and 16.7 months for RT alone.

However, patients receiving TMZ-RT had a longer median overall survival of 34.1 months compared to 27.4 months for those treated with RT alone, suggesting a potential benefit of the combination therapy that warrants further investigation through prospective randomized trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined temozolomide and radiation as an initial treatment for anaplastic glioma. Tham, CK., See, SJ., Tan, SH., et al.[2018]

Citations

1. withpower.com withpower.com/trial/phase-1-glioblastoma-11-2021-50bd0

Ferumoxytol + Vitamin C for Glioblastoma ... The available research does not provide specific data on the effectiveness of Ferumoxytol + Vitamin C for treating Glioblastoma. Instead, the studies focus ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10821426/

MRI Detection and Therapeutic Enhancement of Ferumoxytol ... In vitro T2* mapping successfully detected an AscH−-mediated reduction of ferumoxytol (25.6 ms versus 2.8 ms for FMX alone). The T2* relaxation ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-01753

Pharmacologic Ascorbate and Ferumoxytol Combined with ... Ferumoxytol is an intravenous iron supplement that may make tumor cells more sensitive to pharmacologic ascorbate. Temozolomide is in a class of medications ...

4. clinconnect.io clinconnect.io/trials/NCT04900792

A Safety Study of Pharmacologic Ascorbate and - ClinConnect This clinical trial evaluates adding ferumoxytol and pharamcologic ascorbate (vitamin C) to standard of care treatment of glioblastoma multiforme (a type of ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0891584925009700

Iron-oxide nanoparticles selectively enhance the toxicity of ... The current study shows that 24 h pretreatment with an FDA-approved iron-oxide nanoparticle, Ferumoxytol (FMX), enhances the toxicity of P-AscH- ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10025281/

Magnetite nanoparticles as a kinetically favorable source of ... Ferumoxytol (FMX) is an FDA-approved magnetite (Fe3O4) nanoparticle used to treat iron deficiency anemia that can also be used as an MR imaging ...