Local failure will be defined using the following criteria: For lesions measuring more than 5 mm in the baseline (volumetric) scan: At least 50% increase in the product of the two largest perpendicular diameters (compared to the smallest product measured for the same lesion). For lesions measuring 5 mm or less in the baseline (volumetric) scan: At least 100% increase in the product of the two largest perpendicular diameters (compared to the smallest product measured for the same lesion). Radiation necrosis will not be considered tumor progression.

Lesion-specific tumor control rate is defined as the percent of lesions that do not meet criteria for local failure as defined above.

Local failure will be defined using the following criteria: For lesions measuring more than 5 mm in the baseline (volumetric) scan: At least 50% increase in the product of the two largest perpendicular diameters (compared to the smallest product measured for the same lesion). For lesions measuring 5 mm or less in the baseline (volumetric) scan: At least 100% increase in the product of the two largest perpendicular diameters (compared to the smallest product measured for the same lesion). Radiation necrosis will not be considered tumor progression.

Lesion-specific tumor control rate is defined as the percent of lesions that do not meet criteria for local failure as defined above.

The following tests are included:

• Hopkins Verbal Learning Test (HVLT)
• Controlled Oral Word Association Test (COWAT)
• Trail Making Test Part A
• Trail Making Test Part B
• Grooved Pegboard

HVLT raw scores are derived for Total Recall, Delayed Recall, and Retention (% retained). COWAT is measured by summing the number of acceptable words produced for three separate letters during one minute each. The trail making tests are measured by the time they take to complete. The grooved pegboard is scored by the amount of time it takes to place the pegs correctly in the pegboard. Higher scores on HVLT and COWAT and faster times on the trail making and pegboard indicate better neurocognitive function. All tests are then standardized based on published norms and transformed so that higher values represent improved cognition.

The endpoint is defined as a decline of greater than 1 standard deviation from baseline on at least 1 of the 5 neurocognitive tests.

PROs will be assessed using the MD Anderson Symptom Inventory for brain tumors (MDASI-BT), a validated assessment in people with brain metastases. It is a 28-item questionnaire that includes 13 symptom severity items, 6 symptom interference items, and 9 brain-tumor specific symptom items. Experience of each item "in the last 24 hours" is rated on a 10-point Likert scale where a higher score indicates worse outcomes.

Ratings are averaged into several subscale scores: mean core symptom severity, mean brain tumor symptom severity, and mean interference. The change score from baseline to 24 months will be calculated by subtracting the 12-month overall score from the baseline overall score. Positive values indicate improved outcomes and negative values indicate worse outcomes.

European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 consists of 30 items and measures an individual's functioning and symptoms for all cancer types. Questions are grouped into 5 multi-item functional scales; 3 multi-item symptom scales; a 2-item global health status scale; 5 single items assessing additional symptoms commonly reported by cancer patients, and 1 item on the financial impact of the disease.

Raw QLQ-C30 scores are transformed to standardized scores (0 to 100); a higher score represents a better level of functioning or a worse level of symptoms. A Summary Score is calculated from the mean of 13 of the 15 scales (excluding Global Quality of Life and Financial Impact scales). The symptom scales are reversed to obtain uniform direction of all scales.

The change score from baseline to 24 months will be calculated by subtracting the 24-month score from the baseline score. Negative values indicate improved QOL.

EORTC QLQ-BN 20 consists of 20 items and measures the functioning and symptoms of patients with intracranial malignant disease. Questions can be grouped into 3 multi-item functional scales (visual disorder, motor dysfunction, communication deficit), 7 single items (headaches, seizures, drowsiness, itchy skin, hair loss, weakness of legs and bladder control) and 1 multi-item scale on future uncertainty.

Scoring is on a scale of 0 to 80, with higher scores indicating worse symptoms. The change score from baseline to 24 months will be calculated by subtracting the 24-month score from the baseline score. Positive values indicate improved symptoms.

Inclusion Criteria:

1. Patient must have histologically or cytologically confirmed diagnosis of cancer within the past 5 years. If original histologic proof of malignancy is > 5 years, then biological [such as presence of tumor markers, circulating tumor (ctDNA), etc.], or pathological (i.e., more recent) confirmation is required (e.g., from a systemic metastasis or brain metastasis)
2. Age ≥ 18
3. Karnofsky performance status ≥ 50 or Eastern Cooperative Oncology Group (ECOG) ≥ 3
4. Brain metastasis with a maximum tumor diameter of the largest lesion ≤ 2 cm
5. Patients must have discontinued corticosteroids at least 5 days prior to SRS. (Note: This does not apply to corticosteroids administered as part of this protocol.)
6. Patients must not be pregnant (positive pregnancy test) or breast feeding. Effective contraception (men and women) must be used in patients of child-bearing potential during radiotherapy and for 6 months after.
7. Patients who have received prior SRS are eligible, provided that there are new non-irradiated brain lesions and that the patient is ≥ 2 months post prior cranial radiation therapy
8. Patient has adequate biological parameters as demonstrated by the following blood counts at Screening (obtained ≤ 14 days prior to enrollment):
   • Absolute neutrophil count (ANC) ≥ 1.0 × 109/L
   • Platelet count ≥ 75,000/mm3 (75 × 109/L)
   • Hemoglobin (Hgb) ≥ 9 g/dL without transfusion or growth factor support
9. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L; Platelet count ≥ 75,000/mm3 (75 × 10^9/L); Hemoglobin (Hgb) ≥ 9 g/dL without transfusion or growth factor support
10. Patient has the following blood chemistry levels at Screening (obtained ≤ 14 days prior to enrollment):
    • Aspartate aminotransferase (AST; SGOT), alanine transaminase (ALT; SGPT) ≤ 2.5 × upper limit of normal range (ULN). Total bilirubin ≤ 1.5 × ULN.
    • Estimated creatinine clearance of > 60 mL/min (per Cockcroft-Gault formula)

Exclusion Criteria:

1. Patients with leptomeningeal disease
2. Patients unable to undergo magnetic resonance imaging (MRI)
3. Patients receiving Cytochrome P450 (CYP) 2C8 inhibitors as indicated in the protocol
4. Patients with a gastrointestinal condition that could interfere with swallowing or absorption.
5. Females of childbearing potential who are sexually active or males with female partners of childbearing potential, where either the female or the male is unwilling to use a highly effective method of contraception during the trial and for 6 months after the last administration of azeliragon.
6. 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.
7. Any patient that in the opinion of the principal investigator is not an appropriate candidate for this trial