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

Trial Summary

What is the purpose of this trial?

Single institution study to assess the safety of concurrent Azeliragon with craniospinal irradiation (CSI) in patients with leptomeningeal metastasis from solid tumor malignancies and high-grade gliomas.

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.

What data supports the effectiveness of the treatment Azeliragon + Craniospinal Irradiation for brain cancer spread?

Research on similar treatments shows that combining drugs that can penetrate the brain with radiation therapy can improve outcomes in brain cancer. For example, the drug AZD1390, which enhances the effects of radiation, has shown promise in preclinical models by increasing survival and reducing tumor size. ^{1 2 3 4 5}

Is the combination of Azeliragon and craniospinal irradiation generally safe for humans?

The research articles do not provide specific safety data for the combination of Azeliragon and craniospinal irradiation. However, they discuss potential risks of radiation therapy, such as brainstem toxicity, which can occur when treating brain tumors with high-dose radiation. ^{6 7 8 9 10}

How is the drug Azeliragon unique in treating brain cancer spread?

Azeliragon is unique because it is combined with craniospinal irradiation to target brain cancer spread, potentially offering a novel approach compared to standard treatments like whole-brain irradiation alone. This combination may enhance the effectiveness of radiation therapy by potentially improving drug delivery to the brain. ^{1 2 4 11 12}

Research Team

Jonathan Yang, MD, PhD

Principal Investigator

NYU Langone Health

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

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 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 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]

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]

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]

References

1. Germany 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. [2018]

2. England 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. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Phase I/II trial of simultaneous whole-brain irradiation and dose-escalating topotecan for brain metastases. [2013]

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

The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. [2021]

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

A phase I/II trial of topotecan and radiation therapy for brain metastases in patients with solid tumors. [2013]

6. England pubmed.ncbi.nlm.nih.gov

The incidence of brainstem toxicity following high-dose conformal proton therapy for adult skull-base malignancies. [2022]

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

Quantitative analysis of three-dimensional conformal radiotherapy techniques for posterior fossa treatment in children. [2017]

8. Ireland 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. [2022]

9. United States 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. [2020]

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

Correlation of Acute and Late Brainstem Toxicities With Dose-Volume Data for Pediatric Patients With Posterior Fossa Malignancies. [2018]

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

Orally Bioavailable and Blood-Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice. [2020]

12. England pubmed.ncbi.nlm.nih.gov

Brain exposure of the ATM inhibitor AZD1390 in humans-a positron emission tomography study. [2021]