High-Grade Glioma
Conditions
Brief summary
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.
Interventions
DRUGXRD-0394
Administered orally; small molecule dual inhibitor of ataxia telangiectasia mutated kinase (ATM) and DNA-PK.
RADIATIONRadiation 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.
PROCEDURESurgical Resection
Resection of tumor tissue.
Sponsors
NYU Langone Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants who Experience Dose-Limiting Toxicities (DLTs) | End of DLT Monitoring Period (Pre-surgical dose-escalation: Day 8; Cohort C: Day 44; Cohorts A & B: Day 108) | Assessed among patients who receive at least one dose of the study drug and are evaluated for dose-limiting toxicities (DLTs). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Up to Year 3 Post-Enrollment | Assessed among Cohorts A, B, and C only. Defined as the time from the start of treatment until the first documented disease progression or death. |
| Overall Survival (OS) | Up to Year 3 Post-Enrollment | Assessed among Cohorts A, B, and C only. Defined as the time from treatment initiation until death from any cause. |
| Maximum Concentration (Cmax) of XRD-0394 in Resected Tumor Tissue | Day 8 (Day of Surgery) | Assessed among Pre-Surgical Dose-Escalation participants only. |
| Area Under the Curve (AUC) of XRD-0394 in Resected Tumor Tissue | Day 8 (Day of Surgery) | Assessed among Pre-Surgical Dose-Escalation participants only. |
| Time to Maximum Concentration (Tmax) of XRD-0394 in Resected Tumor Tissue | Day 8 (Day of Surgery) | Assessed among Pre-Surgical Dose-Escalation participants only. |
Countries
United States
Contacts
Primary ContactJonathan Yang, MD, PhD
Backup ContactCancer Trials NYU Langone
Outcome results
None listed