NCT05002140

Trial of XRD-0394, a Kinase Inhibitor, in Combination With Palliative Radiotherapy in Advanced Cancer Patients

A Phase 1, Open-Label, Dose-Finding, Pharmacokinetic, and Pharmacodynamic Study of XRD-0394 in Subjects With Metastatic, Locally Advanced, or Recurrent Cancer Receiving Palliative Radiotherapy

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 12 (actual)
• Sponsor: XRad Therapeutics Inc · Industry
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

XRD-0394 is a novel, potent, oral, small molecule dual inhibitor of ataxia telangiectasia mutated kinase (ATM) and deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PK) that has selectivity compared with other phosphatidylinositol 3-kinase-related kinase (PIKK) family enzymes. This is a first-time-in-human study, which means that it is the first time the study drug is being used in humans. The purpose of the study is to evaluate the safety and tolerability of single doses of XRD-0394 administered with palliative radiotherapy (RT) to subjects with metastatic, locally advanced, or recurrent cancer. The pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of single-dose XRD-0394 administered in combination with palliative RT will also be characterized.

Detailed description

This is a Phase 1, multicenter, open-label, dose-finding, PK and PD study of XRD-0394 in subjects with metastatic, locally advanced, or recurrent cancer receiving palliative RT. The study will evaluate single-dose PK of XRD-0394 administered to serial cohorts of subjects with the intent of identifying an oral dose that achieves plasma drug concentrations within a specified therapeutic range. Once target plasma concentrations of XRD-0394 are reached, one or more PD cohorts of subjects will be enrolled in order to demonstrate inhibition of radiation-induced ATM activity in tumor biopsy samples from subjects who received the selected dose(s). Single Dose Escalation: Eligible subjects will be enrolled in serial cohorts to evaluate the PK of single ascending doses of XRD-0394. Dose escalation of XRD-0394 will proceed based on a standard 3+3 design. The starting dose of XRD-0394 will be 40 mg, followed by planned doses of 80 mg and 160 mg. Following administration of a single-dose of XRD-0394 and completion of RT, subjects will be evaluated for the occurrence of dose-limiting toxicities (DLTs). The available PK and safety data for each cohort will be reviewed at the conclusion of the DLT evaluation period before the decision to escalate to the next dose is made. The evaluation of additional doses of XRD-0394 will be determined based on the safety and PK data collected at completed dose levels. Dose escalation may continue until the objectives of the study are met and/or the maximum tolerated dose (MTD) of XRD-0394 is reached. PK samples for measurement of plasma concentrations of XRD-0394 will be collected pre-dose and at specified time points following XRD-0394 administration. Safety and tolerability of each XRD-0394 dose level will be evaluated by assessment of treatment-emergent adverse events (TEAEs), DLTs, and discontinuations due to TEAEs. A Safety Monitoring Committee (SMC) will be used during the study to monitor subject safety and evaluate potential DLTs. Pharmacodynamic Assessment: The dose identified to produce plasma drug concentrations of XRD-0394 within a targeted therapeutic range will be further evaluated in separate PD cohort(s) of subjects. Subjects enrolled in a PD cohort must have a target tumor with a soft tissue component that is accessible for biopsy and must agree to undergo 1 biopsy during their RT regimen. PK samples for measurement of plasma concentrations of XRD-0394 will be collected from all subjects at pre-dose and at specified time points after XRD-0394 administration. Safety and tolerability of XRD-0394 will be evaluated by assessment of TEAEs.

Conditions

• Metastasis
• Locally Advanced Solid Tumor
• Recurrent Cancer

Interventions

Type	Name	Description
DRUG	XRD-0394	Single ascending dose
RADIATION	Palliative radiotherapy	4 Gy × 5 daily fractions

Timeline

• Start date: 2021-08-24
• Primary completion: 2023-07-21
• Completion: 2023-07-21
• First posted: 2021-08-12
• Last updated: 2024-01-11

Locations

2 sites across 1 country: United States

Regulatory

• FDA-regulated drug study