Concurrent XRD-0394 With Radiation Therapy for High Grade Gliomas

Официальное название

A Phase 0/I Study to Assess the Safety and Tolerability of XRD-0394 in Combination With Radiation Therapy in Patients With High Grade Gliomas

Обзор

This is an open-label, dose-finding study of XRD-0394 in subjects with newly diagnosed and recurrent high grade gliomas receiving radiation therapy, with and without concurrent temozolomide based on O6-Methylguanine-DNA methyltransferase (MGMT) status for patients with newly diagnosed high grade gliomas.

Вмешательства

• Препарат XRD-0394
  Administered orally; small molecule dual inhibitor of ataxia telangiectasia mutated kinase (ATM) and DNA-PK.
• Лучевая терапия Radiation Therapy
  For Cohort A and Cohort B, the neoadjuvant "boost" radiation dose is 1400cGy delivered over 7 fractions, and the adjuvant radiation dose is 5000cGy delivered over 25 fractions for a total dose of 6400cGy over 32 fractions, accounting for the treatment break between boost and adjuvant RT. For Cohort C, the radiation dose is 3500cGy delivered over 10 fractions.
• Процедура Surgical Resection
  Resection of tumor tissue.

Первичные конечные точки

• Number of Participants who Experience Dose-Limiting Toxicities (DLTs) [Срок оценки: End of DLT Monitoring Period (Pre-surgical dose-escalation: Day 8; Cohort C: Day 44; Cohorts A & B: Day 108)]

Вторичные конечные точки (5)

• Progression-Free Survival (PFS) [Срок оценки: Up to Year 3 Post-Enrollment]
• Overall Survival (OS) [Срок оценки: Up to Year 3 Post-Enrollment]
• Maximum Concentration (Cmax) of XRD-0394 in Resected Tumor Tissue [Срок оценки: Day 8 (Day of Surgery)]
• Area Under the Curve (AUC) of XRD-0394 in Resected Tumor Tissue [Срок оценки: Day 8 (Day of Surgery)]
• Time to Maximum Concentration (Tmax) of XRD-0394 in Resected Tumor Tissue [Срок оценки: Day 8 (Day of Surgery)]

Критерии участия

Критерии включения

• Willing and able to provide written informed consent.
• ≥18 years of age.
• For Cohorts A and B, radiographic diagnosis of high-grade glioma that is then confirmed with biopsy. Patients with established histologic diagnosis of high-grade glioma is able to enroll on the study without repeating biopsy.
• For Cohort C, histologic diagnosis of high-grade glioma is required to enroll on the study.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
• Subjects must have adequate liver and kidney function, defined as: Liver transaminase levels ≤2.5 × the upper limit of normal (ULN); total bilirubin ≤1.5 × ULN, except in subjects with Gilbert's Disease in whom total bilirubin ≤5 × ULN is allowed; OR Creatinine clearance ≥60 mL/min measured from a 24-hour urine collection or calculated based on the Cockcroft-Gault formula.
• Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy. Female subjects of childbearing potential who are undergoing RT or who are partners to male subjects in the study should avoid sexual activity or use a highly effective method of birth control during sexual intercourse. Acceptable, highly effective methods of birth control include intrauterine device (IUD)/intrauterine hormone releasing system (IUS), bilateral tube occlusion, vasectomized partner, combined (estrogen and progesterone containing) or progesterone-only hormonal contraceptives (oral, intravaginal, transdermal, injectable).
• Subjects receiving anti-glioma therapy are eligible if treatment can be held 14 days before the first XRD-0394 dose and resume a minimum of 5 days after completion of XRD-0394 (Cohort C only).
• Patient with recurrent tumor amendable to reirradiation and is at least 3 months from end of prior brain radiation therapy (Cohort C only)
• Subjects taking glucocorticoids before and during protocol treatment period will be included per the discretion of the investigator. Intake should be minimized before and during treatment.

Критерии исключения

• Prior radiotherapy to the same region or prior anti-glioma systemic therapy in patients with newly diagnosed HGG (Cohorts A and B, not applicable for Cohort C)
• Subjects with bone marrow impairment as evidenced by hemoglobin <8.0 g/dL, neutrophil count <1.5 × 109/L, or platelets <100 × 109/L.
• History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or condition that may hamper compliance and/or absorption of XRD-0394, use of percutaneous endoscopic gastrostomy (PEG) tubes.
• Significant cardiac conduction abnormalities, including a history of long corrected QT (QTc) interval syndrome (>450 msec per Fridericia's formula) and/or pacemaker, or impaired cardiovascular function such as New York Heart Association classification >2 at screening.
• Participation in another investigational study of an unapproved drug or device or treatment with another ATM, deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PK), or ataxia-telangiectasia and Rad3-related (ATR) inhibitor within 28 days of the first dose of XRD-0394.
• Subjects who are pregnant or breast-feeding.
• Subjects with a QTc interval >450 msec (calculated using Fridericia's QT correction formula) at screening.
• Contraindication to temozolomide (Cohort A only)
• Severe headache, rapidly progressive neurologic decline, objective neurologic manifestations of uncal herniation, depressed level of consciousness
• Subjects receiving treatment with any drug that is a strong inhibitor or inducer of CYP3A4 enzyme activity or an inhibitor of BCRP within a minimum of 5 half- lives or 14 days prior to screening or during study participation.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• NYU Langone Health — New York

Идентификаторы

NCT: NCT06829173 · 24-01715

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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