DFMO + AMXT 1501 for Brain Tumor

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Mayo Clinic

Disqualifiers: Pregnancy, Prisoners, Mental handicap, others

Compensation: Varies

Number of Visits: 1

Duration: 5 days

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to study how specific treatments affect brain tumors known as gliomas. Researchers are testing two treatments: eflornithine (DFMO), which blocks a key enzyme needed for tumor growth, and AMXT 1501 (AMXT 1501 dicaprate), which prevents tumors from absorbing growth-promoting molecules. Participants will undergo surgery and receive these treatments to observe their impact on tumor metabolism. Individuals with a diagnosed or suspected high-grade glioma who are planning to have surgery might be suitable candidates for this trial. As an Early Phase 1 trial, this research focuses on understanding how these new treatments work in people, offering participants the opportunity to be among the first to receive them.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research examines the safety and tolerability of combining DFMO and AMXT 1501 for patients. DFMO, also known as eflornithine, has been used in other treatments, including for neuroblastoma in children. Studies have shown that DFMO is generally well-tolerated and does not present unexpected safety issues when combined with other drugs.

AMXT 1501 is a newer treatment under study for its potential to block molecules that brain tumors need to grow. Although still in early testing, the primary goal is to assess its safety when used with DFMO. Testing proceeds in careful steps to ensure safety before advancing to larger studies.

Early-phase trials focus on ensuring treatments are safe for people. Despite being in the initial stages, there is a strong emphasis on monitoring for side effects and confirming the treatment's safety before administering it to more participants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for brain tumors focus on surgery, radiation, and chemotherapy, which target tumor cells directly. But the combination of DFMO and AMXT 1501 works differently, aiming to disrupt the tumor's growth by targeting polyamine metabolism, a process essential for cancer cell proliferation. DFMO (eflornithine) inhibits an enzyme called ornithine decarboxylase, reducing polyamine production, while AMXT 1501 enhances the uptake of DFMO into cells, potentially boosting its effectiveness. Researchers are excited about these treatments because they offer a novel approach that could complement existing therapies, potentially leading to better outcomes for patients with brain tumors.

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

Research has shown that DFMO, also known as eflornithine, can block the production of polyamines, which cancer cells need to grow. DFMO has shown promise in treating neuroblastoma by slowing tumor growth. In this trial, participants in different arms will receive DFMO combined with AMXT 1501. Studies suggest that AMXT 1501 may further weaken cancer cells by preventing them from absorbing polyamines from outside the cells. This two-part approach aims to cut off the tumor's supply of these crucial molecules, potentially slowing or stopping its growth. Although data on brain tumors is limited, this strategy of disrupting polyamine use shows early promise in cancer treatment. ^{1 6 7 8 9}

Who Is on the Research Team?

Terence C. Burns, MD, PhD

Principal Investigator

Mayo Clinic in Rochester

Are You a Good Fit for This Trial?

This trial is for adults with diffuse or high-grade glioma who can swallow tablets, are not pregnant, and have no allergies to the drugs being tested. They must have proper kidney function, normal blood counts, stable thyroid function, and be able to stay in the hospital for additional days post-surgery.

Inclusion Criteria

My kidney function, measured by creatinine levels, is within the required range.

I have or am suspected to have a high-grade brain tumor.

My hemoglobin level is at least 9 g/dL without recent blood transfusions.

Exclusion Criteria

Contraindication to MRI or administration of gadolinium

Vulnerable populations: pregnant or nursing women, prisoners, mentally handicapped

Patients who are not appropriate surgical candidates due to current or past medical history or uncontrolled concurrent illness which limits safety of or compliance to study proceedings

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgical Resection and Baseline Assessment

Patients undergo surgical resection with MRI and placement of catheters for microdialysis at baseline

1 week

1 visit (in-person)

Treatment

Patients receive DFMO and AMXT 1501 orally post-surgery, with microdialysate collection and CT scans

5 days

Daily visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 months

What Are the Treatments Tested in This Trial?

Interventions

• AMXT-1501 Dicaprate
• DFMO

Trial Overview The study investigates how DFMO (a drug that blocks tumor growth molecules) and AMXT 1501 (which stops tumors from getting these molecules from outside) affect brain tumor metabolism. Participants will undergo surgery, imaging tests like CT/MRI scans, biospecimen collection, and microdialysis.

How Is the Trial Designed?

Group I: Arm I (MRI, resection, DFMO, AMXT 1501) Experimental Treatment 8 Interventions

Patients undergo magnetic resonance imaging (MRI) and surgical resection at baseline. Patients receive eflornithine PO in combination with AMXT 1501 PO on days 1-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.

Group II: Arm III (MRI, resection, DMFO, AMXT 1501) Active Control 8 Interventions

Patients undergo magnetic MRI and surgical resection at baseline. Patients receive eflornithine PO alone on days 1 and 2 post-surgery, then receive eflornithine PO in combination with AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.

Group III: Arm II (MRI, resection, placebo, DMFO, AMXT 1501) Placebo Group 8 Interventions

Patients undergo magnetic MRI and surgical resection at baseline. Patients receive placebo PO on days 1 and 2 post-surgery, and then receive eflornithine PO and AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The study found that the diffusion of DFMO (alpha-[5-14C]-difluoromethylornithine) from blood to brain and cerebrospinal fluid is limited in both rats and beagle dogs, indicating challenges in delivering the drug to these areas.

However, DFMO can effectively diffuse into 9L brain tumors and adjacent brain tissue in rats, suggesting that its therapeutic efficacy is not restricted by transport limitations, as the tissue/plasma ratios were approximately 1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain, CSF, and tumor pharmacokinetics of alpha-difluoromethylornithine in rats and dogs. Levin, VA., Csejtey, J., Byrd, DJ.[2019]

The study presents a novel brain-targeted nanocarrier, DOX-loaded apoferritin, which effectively crosses the blood-brain barrier and targets glioma cells due to its ability to bind to the transferrin receptor 1 (TfR1), which is highly expressed in these cells.

In vivo experiments showed that mice treated with DOX-loaded apoferritin had a significantly longer survival period (30 days) compared to those receiving free doxorubicin (19 days), indicating enhanced therapeutic efficacy of the nanocarrier.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apoferritin Nanocage for Brain Targeted Doxorubicin Delivery. Chen, Z., Zhai, M., Xie, X., et al.[2018]

D,L-alpha-difluoromethylornithine (DFMO) significantly enhances the uptake of [3H] putrescine in gliosarcoma cells, leading to a substantial reduction in cell proliferation and viability, with a 10^10 fold inhibition of colony-forming cells after 20 days of treatment.

The combination of DFMO and [3H] putrescine treatments resulted in a dramatic decrease in surviving colony-forming cells, indicating that DFMO can be cytotoxic to brain tumor cells when used over extended periods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of D,L-alpha-difluoromethylornithine (DFMO) enhanced [3H]putrescine uptake on 9L tumor cell growth and colony forming efficiency. Redgate, ES., Grudziak, A., Floyd, KL., et al.[2019]

In a study involving 38 patients with various cancers, DFMO was added to conventional chemotherapy and showed negligible gastrointestinal, hematologic, and biochemical toxicity, with the main side effect being ototoxicity in 15.8% of patients.

Despite its safety profile, DFMO did not demonstrate any significant improvement in disease progression compared to conventional chemotherapy alone, indicating that it may not enhance the efficacy of standard cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I-II clinical trial with alpha-difluoromethylornithine--an inhibitor of polyamine biosynthesis. Horn, Y., Schechter, PJ., Marton, LJ.[2019]

The newly developed radiotracer [(18)F]FOFA shows significant accumulation in brain tumors during PET scans, indicating its potential as a useful imaging agent for visualizing brain tumors in a rat model.

With a high radiochemical purity of 99% and a specific activity exceeding 22 GBq/μmol, [(18)F]FOFA demonstrates favorable characteristics for molecular imaging, suggesting it could effectively target inflammatory processes in tumor micro-environments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and Biological Evaluation of an (18)Fluorine-Labeled COX Inhibitor--[(18)F]Fluorooctyl Fenbufen Amide--For Imaging of Brain Tumors. Huang, YC., Chang, YC., Yeh, CN., et al.[2020]

Intranasal administration of deferoxamine (DFO) significantly increases its concentration in the brain compared to intravenous delivery, achieving up to 200 times more targeted delivery to the cortex, which is crucial for treating stroke.

In animal studies, both pre-treatment and post-treatment with intranasal DFO reduced stroke damage by 55%, indicating its potential as an effective treatment and preventive measure for ischemic stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. Hanson, LR., Roeytenberg, A., Martinez, PM., et al.[2021]

In a phase I study involving 24 patients, eflornithine-HCl (DFMO) was found to have a maximally tolerated dose of 3.75 gm/M2 every 6 hours for oral administration, with nausea and vomiting being the most common side effects.

Intravenous administration of DFMO resulted in higher plasma levels compared to chronic oral dosing, and no significant thrombocytopenia or audiometric abnormalities were observed, suggesting a potentially safer profile for shorter treatment durations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial and pharmacokinetic study of intravenous and oral alpha-difluoromethylornithine. Griffin, CA., Slavik, M., Chien, SC., et al.[2019]

In a study with Fischer 344 male rats, the polyamine inhibitor difluoromethylornithine (DFMO) significantly reduced tumor growth when combined with an essential amino acid-based total parenteral nutrition (TPN) regimen, indicating enhanced antitumor activity.

However, DFMO caused greater thrombocytopenia (low platelet count) when administered with the essential amino acids compared to a regimen that included nonessential amino acids, suggesting a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced tissue ornithine increases the cytotoxicity of difluoromethylornithine. Grossie, VB., Nishioka, K.[2013]

The study involving 6 healthy controls and 12 patients with brain tumors demonstrated that the amino acid PET tracer O-[18F]fluoromethyl-d-tyrosine (d-18F-FMT) is safe and effectively distinguishes brain tumors from normal brain tissue.

Optimal imaging for brain tumors using d-18F-FMT occurs within 15 minutes post-injection, as the tumor-to-background ratio peaks during this time, allowing for better contrast in PET scans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 0 Microdosing PET/CT Study Using O-[18F]Fluoromethyl-d-Tyrosine in Normal Human Brain and Brain Tumor. Moon, H., Byun, BH., Lim, I., et al.[2023]

The study developed two new amino acid tracers for brain tumor imaging, (S)-[(18)F]FAMHep and (S)-[(18)F]FAHep, and found that (S)-[(18)F]FAHep had significantly higher uptake in normal brain tissue due to its recognition by amino acid transporters, making it a promising candidate for imaging.

In comparison to the established tracer (S)-[(18)F]FET, (S)-[(18)F]FAHep showed similar imaging properties in a mouse model of high-grade glioma, while (S)-[(18)F]FAMHep provided better tumor-to-brain ratios, suggesting potential advantages for both tracers in clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of α-Methyl versus α-Hydrogen Substitution on Brain Availability and Tumor Imaging Properties of Heptanoic [F-18]Fluoroalkyl Amino Acids for Positron Emission Tomography (PET). Bouhlel, A., Alyami, W., Li, A., et al.[2018]

Deferoxamine (DFO) attached to PEG-like nanoprobes (DFO-PNs) shows promise as a therapeutic agent, demonstrating effective accumulation in tumor models and inflammation sites in mice, indicating potential for treating cancer and inflammatory conditions.

The study found that DFO-PNs can be internalized by tumor cells and have tunable pharmacokinetics, suggesting they could be optimized for targeted delivery in various medical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imaging PEG-like nanoprobes in tumor, transient ischemia, and inflammatory disease models. Wilks, MQ., Normandin, MD., Yuan, H., et al.[2018]

Solid microparticles made from chitosan chloride and methyl-β-cyclodextrin effectively enhance the delivery of deferoxamine mesylate (DFO) to the brain, achieving significant uptake into cerebrospinal fluid after nasal administration in rats.

Methyl-β-cyclodextrin (MCD) showed superior performance compared to chitosan chloride (DCH) in promoting DFO permeation, resulting in higher concentrations in the cerebrospinal fluid and a greater systemic bioavailability, indicating its potential for safer and more effective brain-targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Solid microparticles based on chitosan or methyl-β-cyclodextrin: a first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate. Rassu, G., Soddu, E., Cossu, M., et al.[2018]

Difluoromethylornithine (DFMO) works as an irreversible inhibitor of the enzyme ornithine decarboxylase, which is crucial for polyamine synthesis, thereby affecting cell survival and showing potential as an anticancer agent.

DFMO has demonstrated cytostatic activity and effectiveness both as a standalone treatment and in combination with other chemotherapy drugs for certain cancers and leukemias, highlighting its role in cancer treatment and prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Difluoromethylornithine in cancer: new advances. Alexiou, GA., Lianos, GD., Ragos, V., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05500508

Oral AMXT 1501 Dicaprate in Combination With IV DFMO The objective of this study is to determine the safety and tolerability of oral AMXT 1501 dicaprate (AMXT1501) in combination with IV DFMO in patients with ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12451337/

Phase I dose-escalation trial of AMXT 1501 dicaprate plus ... A novel approach to depriving cancer cells of polyamines involves the use of DFMO to block polyamine biosynthesis in combination with AMXT 1501, ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03536728

Oral AMXT 1501 Dicaprate in Combination With DFMO The objective of this study is to determine the safety and tolerability of oral AMXT 1501 dicaprate (AMXT1501) in combination with DFMO in patients with ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40913836/

Phase I dose-escalation trial of AMXT 1501 dicaprate plus ... A novel approach to depriving cancer cells of polyamines involves the use of difluoromethylornithine (DFMO) to block polyamine biosynthesis in ...

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-10375

Intratumoral Extracellular Metabolic Impact of DFMO and ... This trial is being done to analyze how DFMO and AMXT 1501 affect brain tumor metabolism based on the molecules in the tumor's fluid. Eligibility Criteria ...

6. trials.braintumor.org trials.braintumor.org/trials/NCT05500508

Oral AMXT 1501 Dicaprate in Combination With IV DFMO - National ... A Phase 1B/2A study will be conducted to establish safety and dose level of AMXT 1501 dicaprate in combination with IV DFMO, in cancer patients. Recruitment ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10637404/

Glioma Metabolic Feedback In Situ: A First-In-Human ... This pilot Phase 0 study will provide in situ feedback during DFMO + AMXT-1501 treatment to determine how high-grade gliomas respond to polyamine depletion.

8. patents.google.com patents.google.com/patent/US11865095B2/en

US11865095B2 - Combination drug substance of ... The objective of this clinical trial is to determine the safety and tolerability of oral AMXT 1501 dicaprate in combination with DFMO in patients with advanced ...

9. cancer.gov cancer.gov/publications/dictionaries/cancer-drug/def/polyamine-transport-inhibitor-amxt-1501-dicaprate

polyamine transport inhibitor AMXT-1501 dicaprate Upon administration, AMXT-1501 targets, binds to and blocks polyamine transport from the bloodstream into the tumor microenvironment (TME), thereby preventing ...