Clinical trial NCT05789589: Effect of Azeliragon Combined With Stereotactic Radiation Therapy in Patients With Brain Metastases
Official title: A Phase I/II Study to Assess Safety and Preliminary Evidence of a Therapeutic Effect of Azeliragon Combined With Stereotactic Radiation Therapy in Patients With Brain Metastases
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Cancer
Metastasis
Metastatic Cancer
Brain Metastases
Brain Metastases, Adult
Lead sponsor: Baptist Health South Florida
Sponsor class: OTHER
Collaborators: name: Miami Cancer Institute
name: Cantex Pharmaceuticals Inc.
First posted: 2023-03-29
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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 × 10\^9/L
   * Platelet count ≥ 75,000/mm\^3 (75 × 10\^9/L)
   * Hemoglobin (Hgb) ≥ 9 g/dL without transfusion or growth factor support
9. 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
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

Primary outcomes:
measure: Total Dose-Limiting Toxicities (DLTs)
timeFrame: 4 weeks
Secondary outcomes:
measure: CNS treatment-related adverse events
timeFrame: 24 months
measure: Early brain metastases response rate
timeFrame: 8 weeks
measure: Intracranial objective response rate
timeFrame: 6 months
measure: Intracranial objective response rate
timeFrame: 12 months
measure: Lesion-specific local tumor control rate
timeFrame: 6 months
measure: Lesion-specific local tumor control rate
timeFrame: 12 months
measure: Neurocognitive outcomes battery
timeFrame: 24 months
measure: Change in patient-reported outcomes (PROs)
timeFrame: Baseline to 24 months
measure: Change in quality of life (QOL) using EORTC QLQ-C30
timeFrame: Baseline to 24 months
measure: Change in QOL using EORTC QLQ-BN20
timeFrame: Baseline to 24 months
Other outcomes:
Locations:
city: Miami
country: United States
facility: Miami Cancer Institute at Baptist Health, Inc.
state: Florida
Study officials:
affiliation: Miami Cancer Institute at Baptist Health, Inc.
name: Minesh Mehta, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Miami Cancer Institute at Baptist Health, Inc.
name: Yazmin Odia, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.