Concurrent XRD-0394 With Radiation Therapy for High Grade Gliomas

NCT06829173 | Recruiting Early Phase 1 DMC FDA Drug

• 1 other identifier: 24-01715
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

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.

Conditions

High-Grade Glioma

Outcome Measures

Primary Outcomes (1)

• Number of Participants who Experience Dose-Limiting Toxicities (DLTs)

  Assessed among patients who receive at least one dose of the study drug and are evaluated for dose-limiting toxicities (DLTs).

  End of DLT Monitoring Period (Pre-surgical dose-escalation: Day 8; Cohort C: Day 44; Cohorts A & B: Day 108)

Secondary Outcomes (5)

• Progression-Free Survival (PFS)

  Up to Year 3 Post-Enrollment

• Overall Survival (OS)

  Up to Year 3 Post-Enrollment

• Maximum Concentration (Cmax) of XRD-0394 in Resected Tumor Tissue

  Day 8 (Day of Surgery)

• Area Under the Curve (AUC) of XRD-0394 in Resected Tumor Tissue

  Day 8 (Day of Surgery)

• Time to Maximum Concentration (Tmax) of XRD-0394 in Resected Tumor Tissue

  Day 8 (Day of Surgery)

Study Arms (4)

Pre-Surgery Dose-Escalation

EXPERIMENTAL

Patients with newly-diagnosed high grade gliomas (HGG) receiving neoadjuvant radiation therapy (RT) prior to surgical resection will be enrolled in the Pre-Surgical Dose-Escalation arm, at one of two dose levels: Participants enrolled at Pre-Surgical Dose Level 1 (DL1) will receive 160mg daily XRD-0394 on the days of radiation therapy before surgery. Participants enrolled at Pre-Surgery Dose Level 2 (DL2) will receive 300mg daily XRD-0394 on the days of radiation therapy before surgery. All patients enrolled in the pre-surgical dose escalation portion of the study will receive DL1 in the post-surgical dose-escalation portion of the study, but will not be enrolled in the Post-Surgery Dose Escalation arms for purpose of analysis.

Drug: XRD-0394; Radiation: Radiation Therapy; Procedure: Surgical Resection

Cohort A: Post-Surgery Dose Escalation

EXPERIMENTAL

MGMT-methylated patients will be enrolled in Cohort A following surgical resection. Participants enrolled at Post-Surgery Dose-Level 1 (DL1) will receive 160 mg XRD-0394 administered twice weekly, concurrently with radiation therapy. Participants enrolled at Post-Surgery Dose-Level 2 (DL2) will receive 160 mg XRD-0394 administered three times weekly, concurrently with radiation therapy. Participants enrolled at Post-Surgery Dose-Level 3 (DL3) will receive 300 mg XRD-0394 administered three times weekly, concurrently with radiation therapy.

Drug: XRD-0394; Radiation: Radiation Therapy; Procedure: Surgical Resection

Cohort B: Post-Surgery Dose Escalation

EXPERIMENTAL

MGMT-unmethylated patients will be enrolled in Cohort B following surgical resection. Participants enrolled at Post-Surgery Dose-Level 1 (DL1) will receive 160 mg XRD-0394 administered twice weekly, concurrently with radiation therapy. Participants enrolled at Post-Surgery Dose-Level 2 (DL2) will receive 160 mg XRD-0394 administered three times weekly, concurrently with radiation therapy. Participants enrolled at Post-Surgery Dose-Level 2 (DL3) will receive 300 mg XRD-0394 administered three times weekly, concurrently with radiation therapy.

Drug: XRD-0394; Radiation: Radiation Therapy; Procedure: Surgical Resection

Cohort C: Dose-Escalation (No Surgery)

EXPERIMENTAL

Patients with recurrent high-grade glioma (HGG) will be enrolled in Cohort C. Participants enrolled at Dose-Level 1 (DL1) will receive 160 mg XRD-0394 administered twice weekly, concurrently with radiation therapy. Participants enrolled at Dose-Level 2 (DL2) will receive 160 mg XRD-0394 administered three times weekly, concurrently with radiation therapy. Participants enrolled at Dose-Level 2 (DL3) will receive 300 mg XRD-0394 administered three times weekly, concurrently with radiation therapy.

Drug: XRD-0394; Radiation: Radiation Therapy

Interventions

XRD-0394 DRUG

Administered orally; small molecule dual inhibitor of ataxia telangiectasia mutated kinase (ATM) and DNA-PK.

Cohort A: Post-Surgery Dose Escalation; Cohort B: Post-Surgery Dose Escalation; Cohort C: Dose-Escalation (No Surgery); Pre-Surgery Dose-Escalation

Radiation Therapy RADIATION

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.

Cohort A: Post-Surgery Dose Escalation; Cohort B: Post-Surgery Dose Escalation; Cohort C: Dose-Escalation (No Surgery); Pre-Surgery Dose-Escalation

Surgical Resection PROCEDURE

Resection of tumor tissue.

Cohort A: Post-Surgery Dose Escalation; Cohort B: Post-Surgery Dose Escalation; Pre-Surgery Dose-Escalation

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• NYU Langone Health: lead

Study Sites (1)

NYU Langone Health

New York, New York, 10016, United States

RECRUITING

MeSH Terms

Conditions

Glioma

Interventions

Radiotherapy

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Jonathan Yang, MD, PhD

  NYU Langone Health

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jonathan Yang, MD, PhD

CONTACT

212-731-6276; Jonathan.Yang@nyulangone.org

Cancer Trials NYU Langone

CONTACT

cancertrials@nyulangone.org

Study Design

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

Study Record Dates

• First Submitted: February 11, 2025
• First Posted: February 17, 2025
• Study Start: November 5, 2025
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2031
• Last Updated: January 2, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
• Access Criteria: The investigator who proposed to use the data will be granted access upon reasonable request. Requests should be directed to Jonathan.Yang@nyulangone.org. To gain access, data requestors will need to sign a data access agreement. This instance of data sharing will also require separate IRB review as well as review from NYU Langone's DSSB.

Locations

US (1)