Azeliragon + Radiation for Brain Cancer

(ADORATION Trial)

Overseen By Kristy Reyes

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Baptist Health South Florida

Must not be taking: CYP 2C8 inhibitors

Disqualifiers: Leptomeningeal disease, MRI inability, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

46 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether combining azeliragon with stereotactic radiosurgery can safely and effectively shrink brain tumors and maintain control over them for longer periods. Researchers are exploring various treatment plans to identify the safest and most effective option. The trial may suit individuals diagnosed with cancer in the past five years who are now facing brain metastasis, with the largest tumor measuring 2 cm or smaller and not currently on corticosteroids. 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 potentially groundbreaking therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking corticosteroids at least 5 days before the treatment, unless they are part of this trial's protocol. Additionally, you cannot take Cytochrome P450 (CYP) 2C8 inhibitors during the trial.

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

Earlier studies have shown that azeliragon is safe for people with Alzheimer's disease. Over 2,000 patients have used it, and the safety results were encouraging. This drug has undergone many advanced clinical trials, thoroughly testing its safety.

Stereotactic radiosurgery (SRS) is a well-known and safe method for treating brain tumors. Research has shown it works effectively with few side effects. SRS precisely targets the tumor, helping to protect healthy tissue.

The goal of combining azeliragon and SRS is to improve outcomes for brain cancer patients. Both treatments have been well-tolerated in past studies, providing strong safety data for this trial. Always consult your healthcare provider to determine if joining a trial is right for you. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for brain cancer, which often include surgery, chemotherapy, and traditional radiation therapy, the combination of Azeliragon and Stereotactic Radiosurgery (SRS) offers a unique approach. Azeliragon is a drug that targets the receptor for advanced glycation end-products (RAGE), which plays a role in inflammation and tumor growth. This makes it different from conventional treatments that don't specifically target this pathway. Additionally, SRS delivers highly focused radiation to the tumor, potentially minimizing damage to surrounding healthy tissue. Researchers are excited about these treatments because they could provide a more precise and targeted attack on brain tumors, possibly enhancing effectiveness while reducing side effects.

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

In this trial, participants will receive a combination of azeliragon and stereotactic radiosurgery (SRS) to treat brain cancer. Research has shown that azeliragon might help by targeting a protein called RAGE, which contributes to the growth of some cancers like glioblastoma. By blocking RAGE, azeliragon could help control the tumor. SRS, a precise type of radiation therapy, has been found in studies to effectively control brain tumors, with high success rates in keeping them in check. Combining azeliragon with SRS in this trial might enhance the treatment's ability to shrink and manage brain tumors. ^{5 6 7 8 9}

Who Is on the Research Team?

Yazmin Odia, MD

Principal Investigator

Miami Cancer Institute at Baptist Health, Inc.

Minesh Mehta, M.D.

Principal Investigator

Miami Cancer Institute at Baptist Health, Inc.

Are You a Good Fit for This Trial?

This trial is for adults with small brain tumors from cancer spread, who are not pregnant or breastfeeding and agree to use contraception. They should have a certain level of physical function, no recent steroids or other clinical trials, and meet specific blood count and chemistry levels.

Inclusion Criteria

I am not pregnant or breastfeeding and will use effective birth control during and for 6 months after treatment.

My cancer was confirmed by a doctor within the last 5 years, or I have recent proof it's still active.

My largest brain tumor is 2 cm or smaller.

Exclusion Criteria

I have a stomach or intestine condition that affects my eating or digestion.

I have cancer that has spread to the lining of my brain and spinal cord.

Patients with concurrent participation in another interventional clinical trial or use of another investigational agent within 7 days of starting azeliragon. Patients who are participating in non-interventional clinical trials (e.g., QOL, imaging, observational, follow-up studies, etc.) are eligible, regardless of the timing of participation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive azeliragon combined with stereotactic radiosurgery, with potential corticosteroid regimens

4 weeks

Multiple visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including neurocognitive and quality of life assessments

24 months

Extension

Long-term monitoring of neurocognitive outcomes and quality of life changes

24 months

What Are the Treatments Tested in This Trial?

Interventions

• Azeliragon
• Corticosteroid
• Stereotactic Radiosurgery

Trial Overview The study tests the safety and effectiveness of azeliragon in combination with focused radiation therapy (stereotactic radiosurgery) on patients with brain metastases to see if it can shrink tumors and control their growth better.

How Is the Trial Designed?

Group I: Azeliragon and Stereotactic Radiosurgery (SRS) Experimental Treatment 3 Interventions

In the Phase 1 portion of the study, three treatment regimens will be systematically evaluated: 1. Azeliragon + SRS + loading corticosteroid dose (LD) + corticosteroid taper (CT) 2. Azeliragon + SRS + loading corticosteroid dose (LD) 3. Azeliragon + SRS The starting cohort will receive Regimen #2, and depending on the tolerability, participants will be allocated to subsequent cohorts as follows: if Regimen #2 is not well tolerated, participants will be allocated to Regimen #1; if #2 is well tolerated, participants will be allocated to Regimen #3. Once a Regimen has been identified as safe and tolerable, it will be used for the Phase 2 portion of the study.

Who Is Running the Clinical Trial?

Baptist Health South Florida

Lead Sponsor

Trials

54

Recruited

8,100+

Cantex Pharmaceuticals Inc.

Collaborator

Trials

1

Recruited

50+

Miami Cancer Institute

Collaborator

Trials

6

Recruited

950+

Published Research Related to This Trial

Combining CyberKnife stereotactic radiosurgery (SRS) with a dose-dense regimen of temozolomide (TMZ) significantly improved median survival (12 months vs. 7 months) and 6-month progression-free survival (66.7% vs. 18%) in patients with recurrent glioblastoma multiforme (GBM).

While the combination treatment showed better outcomes, over 40% of patients experienced grade 3 hematological toxicity, indicating a need for careful monitoring of side effects in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of CyberKnife re-irradiation and "dose dense" temozolomide for recurrent gliomas. Conti, A., Pontoriero, A., Arpa, D., et al.[2022]

In a study of 106 patients with early-stage non-small cell lung cancer treated with CyberKnife® SBRT, the treatment demonstrated an 88% local control rate at 2 years, indicating its efficacy in managing this type of cancer.

The treatment was associated with low toxicity, with only 20% of patients experiencing mild fatigue and 17% mild dyspnea, and only 4% experiencing significant late effects, suggesting it is a safe option for medically inoperable patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk-adapted robotic stereotactic body radiation therapy for inoperable early-stage non-small-cell lung cancer. Temming, S., Kocher, M., Stoelben, E., et al.[2022]

Stereotactic radiotherapy is a highly precise treatment for brain metastases, delivering high doses in a limited number of sessions, which can improve overall survival in patients with a good performance status and limited brain metastases.

It is recommended for specific cases, such as recurrence after whole brain radiotherapy or after surgical resection of large metastases, and aims to delay whole brain radiotherapy to reduce neurotoxicity while maintaining effective control of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Stereotactic radiotherapy in brain metastases]. Dhermain, F., Reyns, N., Colin, P., et al.[2018]

Stereotactic radiosurgery (SRS) effectively controlled tumor growth or arteriovenous malformations (AVMs) in all 78 patients studied, with radiological regression observed in 20 cases after 12 months, particularly in AVMs, meningiomas, and acoustic neuromas.

No new permanent deficits or complications requiring medication were reported, indicating a high safety profile for SRS in treating these cerebral lesions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary results of linac-based radiosurgery in arteriovenous malformations and cerebral tumours in the Oncology Centre in Bydgoszcz. Sokal, P., Lebioda, A., Harat, M., et al.[2021]

Stereotactic radiotherapy, introduced in 2014, was safely administered to 10 patients with brain metastases, showing no significant treatment-related toxicity and excellent overall tolerance.

The treatment demonstrated effective patient immobilization and accurate survival predictions using prognostic indices, suggesting that patients with brain metastases who are fit should be considered for this localized radiation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy management of brain metastases using conventional linear accelerator. Matzenauer, M., Vrana, D., Vlachova, Z., et al.[2019]

In a study of 4,327 patients with brain metastases from non-small cell lung cancer, it was found that treatment at non-academic facilities significantly increased the likelihood of receiving LINAC SRS over Gamma Knife SRS, especially in the Midwestern, Northeastern, and Southern US regions.

Patients receiving higher doses of radiation (18-24 Gy) were also more likely to receive LINAC SRS, and those living within 20 miles of a treatment facility had a 27% higher chance of receiving LINAC, suggesting that geographic accessibility plays a role in treatment modality choice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of linear accelerator versus Gamma Knife stereotactic radiosurgery use for brain metastases in the United States. McClelland Iii, S., Degnin, C., Chen, Y., et al.[2022]

Stereotactic radiosurgery (SRS) is an effective non-invasive technique for targeting deep brain lesions with high doses of radiation, but it does not provide benefits for newly diagnosed malignant gliomas.

For patients with brain metastases, SRS can improve median survival when combined with whole-brain radiation therapy (WBRT), and in some cases, SRS alone may be a viable treatment option without compromising survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of radiosurgery in the management of malignant brain tumors. Stieber, VW., Ellis, TL.[2019]

Gamma knife radiosurgery (GKRS) shows high efficacy in treating trigeminal schwannomas, with a local control rate of 94% and a tumor regression rate of 63% based on a meta-analysis of 19 studies involving 504 patients.

The study indicates that GKRS can be used effectively as both a primary treatment and an adjunct to surgery, but further randomized controlled trials are necessary to fully assess its safety and benefit-to-risk ratio.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gamma knife radiosurgery for trigeminal schwannomas: A systematic review and meta-analysis. Yang, S., Wang, J., Li, X., et al.[2022]

In a study of 127 patients treated with LINAC-based stereotactic radiosurgery (SRS) for benign brain tumors over 20 years, the overall tumor control rate was an impressive 92.9%, indicating high efficacy in managing tumor growth.

The treatment was associated with low neurological morbidity, with only one case of mild cranial nerve injury and no treatment-related mortality, highlighting its safety as a noninvasive option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes of benign brain tumors treated with single fraction LINAC-based stereotactic radiosurgery: Experience of a single institute. Chew, CH., Chen, JC., Hung, SK., et al.[2023]

In a study of 58 patients with malignant gliomas treated with stereotactic radiosurgery (SRS), 47.1% experienced local recurrence within the radiation field, indicating some localized effectiveness of SRS.

However, over half of the patients (52.9%) showed disease progression outside the SRS treatment area, suggesting that SRS alone does not significantly improve overall survival and highlighting the need for a multidisciplinary approach in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pattern of disease progression following stereotactic radiosurgery in malignant glioma patients. Choi, SW., Cho, KR., Choi, JW., et al.[2020]

Stereotactic radiosurgery, particularly using high-energy X-rays and the gamma-knife technique, has become a promising treatment for conditions like arteriovenous malformations and certain slow-growing brain tumors, thanks to advancements in neuro-imaging and radiation delivery methods.

This treatment can be used alone or in combination with other therapies, such as surgery and embolization, and is effective for well-defined, deep-seated tumors, making it a valuable option for carefully selected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactically guided radiosurgery using the linear accelerator. Blond, S., Coche-Dequeant, B., Castelain, B.[2020]

A new planning workflow for intracranial stereotactic radiation therapy (SRT) using a ring gantry linear accelerator (RGLA) was developed and successfully met departmental standards for target coverage and sparing of healthy brain tissue, showing comparable quality to traditional methods.

The RGLA approach not only maintained effective treatment outcomes but also reduced delivery times by approximately 50%, potentially making SRT more accessible to various treatment centers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracranial Stereotactic Radiation Therapy With a Jawless Ring Gantry Linear Accelerator Equipped With New Dual Layer Multileaf Collimator. Knutson, NC., Kennedy, WR., Reynoso, FJ., et al.[2022]

In a study of 173 patients with resected metastatic brain disease, a 3 mm uniform expansion of the stereotactic radiation surgery (SRS) target volume significantly improved coverage of recurrent tumors, potentially enhancing local control rates.

The analysis revealed that the original SRS target volume only overlapped 69.6% of recurrent tumors, but with a 3 mm expansion, this coverage increased to 90%, suggesting that adjusting target volumes could optimize treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local recurrence patterns after postoperative stereotactic radiation surgery to resected brain metastases: A quantitative analysis to guide target delineation. Gui, C., Moore, J., Grimm, J., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02080364

Study Details | NCT02080364 | Evaluation of the Efficacy ... This is a study to evaluate the efficacy and safety of azeliragon in patients with mild Alzheimer's disease.

2. onclive.com onclive.com/view/fda-grants-orphan-drug-designation-to-azeliragon-for-gbm

FDA Grants Orphan Drug Designation to Azeliragon for ... By preventing interaction of RAGE with these ligands, azeliragon may inhibit glioblastoma and overcome its resistance to effective treatment.

3. targetedonc.com targetedonc.com/view/fda-okays-phase-2-study-of-azeliragon-for-patients-with-glioblastoma

FDA Okays Phase 2 Study of Azeliragon for Patients With ... Based on the FDA's review of a new drug application, a phase 2 study will evaluate the safety and efficacy of azeliragon for patients with glioblastoma.

4. nature.com nature.com/articles/s41523-023-00564-9

RAGE inhibitor TTP488 (Azeliragon) suppresses ... These results show that TTP488 impairs metastasis of TNBC and further clarifies the signaling and cellular mechanisms through which RAGE mediates metastasis.

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

azeliragon (TTP488) / vTv Therapeutics, Cantex Pharma Clinical • Combination therapy • P1/2 data • Alzheimer's Disease • Brain Cancer • CNS Disorders • CNS Tumor • Epilepsy • Glioblastoma • Oncology • Solid Tumor • ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05789589

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 ...

7. onclive.com onclive.com/view/fda-grants-orphan-drug-designation-to-azeliragon-for-pancreatic-cancer

FDA Grants Orphan Drug Designation to Azeliragon for ... Safety data from previous clinical trials evaluating the agent in patients with Alzheimer's disease have demonstrated that azeliragon is well ...

8. aacrjournals.org aacrjournals.org/cancerres/article/83/5_Supplement/P4-08-10/717057/Abstract-P4-08-10-Azeliragon-TTP488-an-orally

Abstract P4-08-10: Azeliragon (TTP488), an orally- available ... Importantly, TTP488 displays a high safety profile in human trials and has previously undergone Phase 3 clinical trials for Alzheimer's disease.

9. targetedonc.com targetedonc.com/view/fda-grants-orphan-drug-designation-to-azeliragon-for-patients-with-glioblastoma

FDA Grants Orphan Drug Designation to Azeliragon for ... In previous trials which evaluated azeliragon in over 2000 patients with Alzheimer's, clinical safety data were promising and showed the agent ...