Azeliragon + Craniospinal Irradiation for Brain Cancer Spread

Overseen By Cancer Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: NYU Langone Health

Disqualifiers: Life expectancy < 2 months, Extensive systemic disease, Inability to undergo MRI, Active infection, Serious medical or psychiatric illness, others

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

Compensation: Varies

Number of Visits: Unknown

32 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for individuals with certain types of brain cancer that have spread to the fluid around the brain and spine. It aims to determine if adding Azeliragon (also known as TTP 488) to craniospinal irradiation is safe for patients. The study seeks participants with brain cancers such as high-grade gliomas or solid tumors that have spread, who are already candidates for radiation therapy. Participants will begin taking Azeliragon a week before their radiation treatment and continue through the process to evaluate how the two work together. As a Phase 1 trial, this research focuses on understanding how the treatment functions in people, offering participants the opportunity to be among the first to receive this new therapy.

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 Azeliragon and craniospinal irradiation are likely to be safe?

Research suggests that using azeliragon with craniospinal irradiation (CSI) might be safe and manageable for treating cancer that has spread to the brain or spine, or for aggressive brain tumors. Other studies have examined azeliragon with different types of radiation, indicating this combination could be tolerable for patients.

As this trial is in the early stages, it primarily focuses on how well patients tolerate the treatment. Researchers closely monitor for any side effects to ensure its safety for future use. Although detailed safety information from this trial is not yet available, testing azeliragon in humans indicates some initial confidence in its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for brain cancer spread, which often rely on chemotherapy and traditional radiation, Azeliragon offers a unique approach by targeting the RAGE (Receptor for Advanced Glycation End-products) pathway. This pathway is implicated in inflammation and cancer progression, and Azeliragon's ability to inhibit it could potentially reduce tumor growth and spread more effectively. Researchers are excited about Azeliragon because it not only targets this novel pathway but is also used in combination with craniospinal irradiation, potentially enhancing the overall treatment efficacy while monitoring for toxicity.

What evidence suggests that Azeliragon combined with craniospinal irradiation could be effective for brain cancer spread?

Studies have shown that azeliragon targets a specific pathway involved in inflammation and cancer growth. This pathway plays a crucial role in diseases like glioblastoma, a type of brain cancer. Research suggests that blocking this pathway may help azeliragon slow the spread of cancer cells in the brain. Although limited information exists on its effectiveness against cancer spreading to the membranes around the brain and spinal cord, its ability to reduce inflammation could be beneficial. This trial will use azeliragon in combination with craniospinal irradiation, a type of targeted radiation therapy, to evaluate its effectiveness. Early findings indicate it might be effective when combined with treatments like craniospinal irradiation. ^{1 3 5 6 7}

Who Is on the Research Team?

Jonathan Yang, MD, PhD

Principal Investigator

NYU Langone Health

Are You a Good Fit for This Trial?

This trial is for patients with leptomeningeal metastasis from solid tumors or high-grade gliomas. Specific eligibility details are not provided, but typically participants must meet certain health criteria and may be excluded based on factors that could interfere with the study's safety or results.

Inclusion Criteria

Patient has been informed about the study, agreed to participate, and signed the Informed Consent Form (ICF) prior to participation in any study-related activities

Patients with specific blood count criteria met (ANC ≥ 1.0 × 10^9/L, platelet count ≥ 75,000/mm^3, hemoglobin ≥ 8 g/dL)

My liver and kidney functions are within safe levels.

Exclusion Criteria

Patients unable to complete the English quality of life questionnaires

I have widespread disease and have chosen not to undergo standard treatments.

Patient who is unable to undergo MRI brain and spine with gadolinium contrast

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Determination

Patients start Azeliragon 7 days prior to CSI, during CSI, and for 7 days after completion of CSI. Monitored for dose limiting toxicities.

4 weeks

Dose Expansion

Additional patients treated with Azeliragon at recommended dose in combination with craniospinal irradiation.

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including CNS progression-free survival and overall survival.

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Azeliragon
• Craniospinal Irradiation

Trial Overview The study is testing the safety of using Azeliragon medication in combination with craniospinal irradiation (CSI), a type of radiation therapy, in treating brain cancer and related conditions.

How Is the Trial Designed?

Group I: Dose Determination followed by Dose Expansion Experimental Treatment 2 Interventions

Patients with leptomeningeal metastasis from a solid tumor or primary CNS high-grade glioma will be enrolled and start Azeliragon 7 days prior to CSI, during CSI, and for 7 days days after completion of CSI (Dose Determination). Patients will be monitored for dose limiting toxicities during protocol therapy. Once the recommended dose is identified, additional patients will be treated with Azeliragon at recommended dose in combination with craniospinal irradiation (Dose Expansion).

Who Is Running the Clinical Trial?

NYU Langone Health

Lead Sponsor

Trials

1,431

Recruited

838,000+

Published Research Related to This Trial

In a study of 60 pediatric patients treated with intensity modulated radiation therapy (IMRT) for posterior fossa tumors, 23.3% developed symptomatic brainstem toxicity, indicating a low but significant risk of radiation-induced damage.

No specific dose-volume correlations were found to predict brainstem toxicity, but a trend suggested that vascular injury or ischemia may be predictive, highlighting the need for further research into biological sensitivity and treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlation of Acute and Late Brainstem Toxicities With Dose-Volume Data for Pediatric Patients With Posterior Fossa Malignancies. Nanda, RH., Ganju, RG., Schreibmann, E., et al.[2018]

AZD1390 is a highly selective ATM inhibitor that effectively penetrates the blood-brain barrier and enhances the effectiveness of radiation therapy in treating brain tumors, as demonstrated in preclinical models.

In combination with radiation, AZD1390 significantly increased tumor regression and survival rates in animal models of glioma and lung-brain metastases, indicating its potential as a promising treatment for central nervous system malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Durant, ST., Zheng, L., Wang, Y., et al.[2021]

AZD1390, a selective ATM inhibitor, successfully crossed the blood-brain barrier in a study involving 8 healthy male subjects, indicating its potential for treating brain tumors like glioblastoma multiforme.

The study found no adverse events related to AZD1390, suggesting it is safe for use, and the PET imaging results provide valuable data for optimizing dosing in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain exposure of the ATM inhibitor AZD1390 in humans-a positron emission tomography study. Jucaite, A., Stenkrona, P., Cselényi, Z., et al.[2021]

A consensus among 24 international radiation-oncology experts has led to the development of standardized recommendations for evaluating treatment-related toxicity in adult brain tumor patients after radiotherapy, addressing a gap in the literature.

These recommendations include a structured framework for toxicity scoring and follow-up, which will help in collecting uniform data and enhance collaboration in research on radiation-induced toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Particle Therapy Network (EPTN) consensus on the follow-up of adult patients with brain and skull base tumours treated with photon or proton irradiation. De Roeck, L., van der Weide, HL., Eekers, DBP., et al.[2022]

In a phase II clinical trial involving 76 patients with brain metastases from lung cancer, the combination of whole-brain irradiation, a 3-D conformal boost, and concurrent topotecan chemotherapy significantly improved progression-free survival (PFS) and intracranial lesion control rates compared to radiotherapy alone.

The median PFS for the combined treatment group was 6 months with a 1-year PFS rate of 42.8%, while the radiotherapy-only group had a median PFS of 3 months and a 1-year PFS rate of 11.6%, indicating a notable efficacy of the combined approach without a significant increase in side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II clinical trial of whole-brain irradiation plus three-dimensional conformal boost with concurrent topotecan for brain metastases from lung cancer. Ge, XH., Lin, Q., Ren, XC., et al.[2022]

A systematic analysis of various beam configurations for treating tumors in the posterior fossa revealed that no single ideal photon beam arrangement exists, but specific beams can be optimized to minimize damage to critical normal tissues.

Using 3-D conformal techniques, treatment plans can be tailored based on individual patient characteristics and normal tissue tolerance, which is especially important in pediatric patients to avoid long-term side effects from radiation exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative analysis of three-dimensional conformal radiotherapy techniques for posterior fossa treatment in children. Timmerman, RD., Ewing, M., Donges, M., et al.[2017]

In a retrospective analysis of three patients who experienced treatment-related toxicities after intracranial proton therapy, it was found that the relative biological effectiveness (RBE) in the areas of toxicity was significantly higher than expected, leading to increased radiation doses and normal tissue complication probabilities (NTCP).

Multi-field optimized (MFO) treatment plans were developed that successfully reduced the dose-averaged linear energy transfer (LETd), RBE-weighted dose (DRBE), and NTCP in critical organs at risk, suggesting that these strategies could minimize toxicity without compromising the effectiveness of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spatial correlation of linear energy transfer and relative biological effectiveness with suspected treatment-related toxicities following proton therapy for intracranial tumors. Ödén, J., Toma-Dasu, I., Witt Nyström, P., et al.[2020]

In a study of 31 patients with melanoma that had spread to the brain, the combination of whole brain irradiation (WBI) and temozolomide (TMZ) showed limited antitumor activity, with only one complete response lasting 4.5 months and two partial responses lasting 2 and 7 months.

While the treatment was generally safe, with only a few instances of significant toxicity, the median survival was only 6 months, indicating that WBI combined with TMZ may not be effective for improving outcomes in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group. Margolin, K., Atkins, B., Thompson, A., et al.[2018]

In a phase I/II trial involving 47 patients with inoperable brain metastases, the maximum tolerated dose of topotecan given daily alongside whole-brain radiation therapy (WBRT) was determined to be 12 x 0.5 mg/m² for chemotherapy-naive patients, with significant hematologic toxicities observed in those with prior chemotherapy.

The treatment resulted in a 58% overall response rate, with a median survival of 5.1 months, indicating potential efficacy of topotecan in enhancing the effects of WBRT, warranting further investigation in a phase III trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II trial of simultaneous whole-brain irradiation and dose-escalating topotecan for brain metastases. Kocher, M., Eich, HT., Semrau, R., et al.[2013]

In a phase I/II trial involving 75 patients with brain metastases, the combination of whole-brain radiotherapy (WBRT) and the chemotherapy drug topotecan showed a promising overall response rate of 72%, indicating potential effectiveness in this challenging patient population.

The study found that the recommended dosage of topotecan was 0.4 mg/m²/day due to higher toxicity at 0.5 mg/m²/day, with moderate side effects occurring in 19% of patients, suggesting that while the treatment is effective, careful monitoring of toxicity is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/II trial of topotecan and radiation therapy for brain metastases in patients with solid tumors. Hedde, JP., Neuhaus, T., Schüller, H., et al.[2013]

In a study of 163 patients treated with high-dose conformal proton therapy for skull-base tumors, the incidence of significant brainstem toxicity (grade ≥2) was very low at only 1.3% over a median follow-up of 4 years.

The results suggest that small volumes of the brainstem can safely receive doses of at least 64 GyRBE during treatment, indicating that proton therapy can be an effective and safe option for patients with skull-base chordoma and chondrosarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The incidence of brainstem toxicity following high-dose conformal proton therapy for adult skull-base malignancies. Holtzman, AL., Rutenberg, MS., De Leo, AN., et al.[2022]

The study identified two ATM inhibitors, AZ31 and AZ32, with AZ32 showing improved ability to penetrate the blood-brain barrier and effectively radiosensitize glioblastoma multiforme (GBM) cells in vivo, leading to enhanced tumor control.

AZ32 demonstrated a significant increase in apoptosis in tumor cells compared to healthy brain tissue after radiation treatment, suggesting it could improve survival rates in GBM patients while potentially allowing for lower radiation doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Orally Bioavailable and Blood-Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice. Karlin, J., Allen, J., Ahmad, SF., et al.[2020]

Citations

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Study Details | NCT05789589 | Effect of Azeliragon ... To determine the safety and efficacy of using the drug azeliragon combined with stereotactic radiosurgery. Specifically, to determine if this combination ...

2. delta.larvol.com delta.larvol.com/Products/?ProductId=88868611-da9c-43ee-96e0-1458c828ac67

azeliragon (TTP488) / vTv Therapeutics, Cantex Pharma RAGE signaling pathway in glioblastoma and cognitive decline: Insights into inflammatory mechanisms and therapeutic implications.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4217477/

Leptomeningeal Metastases in High-Grade Adult Glioma Leptomeningeal metastases (LM) in the setting of glioma have often been thought to carry a particularly poor prognosis.

4. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/mco2.70020

Metastatic brain tumors: from development to cutting‐edge ... This abstract briefly reviews the diagnosis and treatment of brain metastases from lung cancer and breast cancer, the progress of artificial ...

5. oncotarget.com oncotarget.com/article/18478/text/

High-grade glioma in very young children: a rare and ... The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2025-01233

Azeliragon With Craniospinal Irradiation for the Treatment ... Giving azeliragon with CSI may be safe, tolerable, and/or effective in treating leptomeningeal metastasis from solid tumor cancer or high-grade gliomas.

7. clinicaltrials.med.nyu.edu clinicaltrials.med.nyu.edu/cancer/clinicaltrial/2624/phase-ib-study-assess/

Perlmutter Cancer Center - Clinical Research Studies - NYU This study is a Phase 1b clinical trial at a single hospital to test the tolerability and safety of combining the drug Azeliragon with craniospinal ...