Effect of Azeliragon Combined With Stereotactic Radiation Therapy in Patients With Brain Metastases

NCT05789589 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 2022-KOT-002
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

To determine the safety and efficacy of using the drug azeliragon combined with stereotactic radiosurgery. Specifically, to determine if this combination will lead to improved response in the brain (tumor shrinking in size) and overall tumor control (how long tumor remains controlled).

Conditions

Cancer; Metastasis; Metastatic Cancer; Brain Metastases; Brain Metastases, Adult

Outcome Measures

Primary Outcomes (1)

• Total Dose-Limiting Toxicities (DLTs)

  A DLT of the azeliragon and corticosteroid regimen is defined as any central nervous system (CNS)-specific Grade ≥ 2 toxicity requiring corticosteroid treatment or any Grade ≥ 3 events that are not clearly due to the underlying disease or extraneous causes. DLTs will be considered up to four weeks after SRS.

  4 weeks

Secondary Outcomes (10)

• CNS treatment-related adverse events

  24 months

• Early brain metastases response rate

  8 weeks

• Intracranial objective response rate

  6 months

• Intracranial objective response rate

  12 months

• Lesion-specific local tumor control rate

  6 months

Study Arms (1)

Azeliragon and Stereotactic Radiosurgery (SRS)

EXPERIMENTAL

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.

Drug: Azeliragon; Radiation: Stereotactic radiosurgery; Drug: Corticosteroid

Interventions

Azeliragon DRUG

Dosing will begin on Day 0 with the loading dose and continue daily through Day 7. Starting on Day 8, dosing will resume with the continuous dose until disease progression or 8 weeks. If there is evidence of antitumor effect at 8 weeks, dosing may continue for up 2 two years. All doses are taken orally. There are three levels of dosing, including a starting dose and two lower levels of dosing. Participants will start with the starting dose, and in the event of the dose limiting toxicities, the dose will be reduced as described below. Starting Dose Level: 30 mg twice daily (Loading Dose) or 20 mg once daily (Continuous Dose) Dose Level -1: 15 mg twice daily (Loading Dose) or 10 mg once daily (Continuous Dose) Dose Level -2: 15 mg once daily (Loading Dose) or 5 mg once daily (Continuous Dose)

Also known as: TTP488, PF-04494700

Azeliragon and Stereotactic Radiosurgery (SRS)

Stereotactic radiosurgery RADIATION

Patients will undergo standard of care SRS as per the treating facility's policies.

Azeliragon and Stereotactic Radiosurgery (SRS)

Corticosteroid DRUG

Two corticosteroid regimens are used depending on the study cohort. Cohorts 1 and 2 will receive the loading dose (LD). Only Cohort 1 will receive the corticosteroid taper (CT). LD: Oral (8 mg) or IV bolus dose (10 mg) of dexamethasone or 40 to 80 mg of methylprednisolone on the day of SRS CT: Oral 2-4 mg of dexamethasone twice daily for 5 days and then 2-4 mg daily for 5 days at the discretion of the treating physician (concurrent use of a proton pump inhibitor or H2 receptor antagonists are encouraged during the CT).

Also known as: dexamethasone, methylprednisolone

Azeliragon and Stereotactic Radiosurgery (SRS)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• Age ≥ 18
• Karnofsky performance status ≥ 50 or Eastern Cooperative Oncology Group (ECOG) ≤ 3
• Brain metastasis with a maximum tumor diameter of the largest lesion ≤ 2 cm
• 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.)
• 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.
• 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
• 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 × 10\^9/L
• Platelet count ≥ 75,000/mm\^3 (75 × 10\^9/L)
• Hemoglobin (Hgb) ≥ 9 g/dL without transfusion or growth factor support
• Absolute neutrophil count (ANC) ≥ 1.0 × 10\^9/L; Platelet count ≥ 75,000/mm\^3 (75 × 10\^9/L); Hemoglobin (Hgb) ≥ 9 g/dL without transfusion or growth factor support
• 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)

You may not qualify if:

• Patients with leptomeningeal disease
• Patients unable to undergo magnetic resonance imaging (MRI)
• Patients receiving Cytochrome P450 (CYP) 2C8 inhibitors as indicated in the protocol
• Patients with a gastrointestinal condition that could interfere with swallowing or absorption.
• 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.
• 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.
• Any patient that in the opinion of the principal investigator is not an appropriate candidate for this trial

Sponsors & Collaborators

• Baptist Health South Florida: lead
• Miami Cancer Institute: collaborator
• Cantex Pharmaceuticals Inc.: collaborator

Study Sites (1)

Miami Cancer Institute at Baptist Health, Inc.

Miami, Florida, 33176, United States

RECRUITING

Related Publications (6)

• Chen X, Zhang L, Zhang IY, Liang J, Wang H, Ouyang M, Wu S, da Fonseca ACC, Weng L, Yamamoto Y, Yamamoto H, Natarajan R, Badie B. RAGE expression in tumor-associated macrophages promotes angiogenesis in glioma. Cancer Res. 2014 Dec 15;74(24):7285-7297. doi: 10.1158/0008-5472.CAN-14-1240. Epub 2014 Oct 17.

  PMID: 25326491 BACKGROUND

• van Grinsven EE, Nagtegaal SHJ, Verhoeff JJC, van Zandvoort MJE. The Impact of Stereotactic or Whole Brain Radiotherapy on Neurocognitive Functioning in Adult Patients with Brain Metastases: A Systematic Review and Meta-Analysis. Oncol Res Treat. 2021;44(11):622-636. doi: 10.1159/000518848. Epub 2021 Sep 3.

  PMID: 34482312 BACKGROUND

• Yang L, Liu Y, Wang Y, Li J, Liu N. Azeliragon ameliorates Alzheimer's disease via the Janus tyrosine kinase and signal transducer and activator of transcription signaling pathway. Clinics (Sao Paulo). 2021 Mar 8;76:e2348. doi: 10.6061/clinics/2021/e2348. eCollection 2021.

  PMID: 33681944 BACKGROUND

• Davis HM, Essex AL, Valdez S, Deosthale PJ, Aref MW, Allen MR, Bonetto A, Plotkin LI. Short-term pharmacologic RAGE inhibition differentially affects bone and skeletal muscle in middle-aged mice. Bone. 2019 Jul;124:89-102. doi: 10.1016/j.bone.2019.04.012. Epub 2019 Apr 24.

  PMID: 31028960 BACKGROUND

• Riuzzi F, Sorci G, Sagheddu R, Chiappalupi S, Salvadori L, Donato R. RAGE in the pathophysiology of skeletal muscle. J Cachexia Sarcopenia Muscle. 2018 Dec;9(7):1213-1234. doi: 10.1002/jcsm.12350. Epub 2018 Oct 18.

  PMID: 30334619 BACKGROUND

• Chiappalupi S, Sorci G, Vukasinovic A, Salvadori L, Sagheddu R, Coletti D, Renga G, Romani L, Donato R, Riuzzi F. Targeting RAGE prevents muscle wasting and prolongs survival in cancer cachexia. J Cachexia Sarcopenia Muscle. 2020 Aug;11(4):929-946. doi: 10.1002/jcsm.12561. Epub 2020 Mar 11.

  PMID: 32159297 BACKGROUND

Related Links

• Miami Cancer Institute

MeSH Terms

Conditions

Neoplasms; Neoplasm Metastasis; Brain Neoplasms

Interventions

azeliragon; Radiosurgery; Adrenal Cortex Hormones; Dexamethasone; Methylprednisolone

Condition Hierarchy (Ancestors)

Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Prednisolone

Study Officials

• Minesh Mehta, M.D.

  Miami Cancer Institute at Baptist Health, Inc.

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Minesh Mehta, M.D.

CONTACT

(786) 596-2000; mineshm@baptisthealth.net

Kristy Reyes

CONTACT

(786) 596-2000; Kristina.Reyes@baptisthealth.net

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 16, 2023
• First Posted: March 29, 2023
• Study Start: November 17, 2023
• Primary Completion (Estimated): March 16, 2027
• Study Completion (Estimated): August 1, 2027
• Last Updated: March 4, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)