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

NCT05002140 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: X0394-001
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Metastasis; Locally Advanced Solid Tumor; Recurrent Cancer

Keywords

Ataxia telangiectasia mutated kinase; ATM; DNA-PK; DNA-dependent protein kinase; Dual inhibitor; Cancer; Palliative radiotherapy; Single dose

Outcome Measures

Primary Outcomes (2)

• Number of subjects with at least 1 dose-limiting toxicity (DLT)

  28 days post-completion of RT

• Number of subjects experiencing treatment-emergent adverse events (TEAE), serious TEAEs, TEAEs leading to discontinuation of RT, and TEAEs leading to death

  28 days post-completion of RT

Secondary Outcomes (8)

• Identification of dose(s) of XRD-0394 that achieve concentrations within protocol-specified range

  Day 2 of RT regimen

• Determination of maximum plasma concentration (Cmax) after a single dose of XRD-0394

  Day 2 through Day 5 of RT regimen

• Determination of plasma concentrations at 1 to 4 hours post-dose after a single dose of XRD-0394

  Day 2 through Day 5 of RT regimen

• Determination of time to maximum plasma concentration (tmax) after a single dose of XRD-0394

  Day 2 through Day 5 of RT regimen

• Determination of area under the plasma concentration versus time curve from zero to the last sampling time (AUC0-t) after a single dose of XRD-0394

  Day 2 through Day 5 of RT regimen

Study Arms (4)

XRD-0394 40 mg

EXPERIMENTAL

Subjects will receive a single dose of XRD-0394 capsules approximately 90 minutes before RT on Day 2 of the RT regimen

Drug: XRD-0394; Radiation: Palliative radiotherapy

XRD-0394 80 mg

EXPERIMENTAL

Subjects will receive a single dose of XRD-0394 capsules approximately 90 minutes before RT on Day 2 of the RT regimen

Drug: XRD-0394; Radiation: Palliative radiotherapy

XRD-0394 160 mg

EXPERIMENTAL

Subjects will receive a single dose of XRD-0394 capsules approximately 90 minutes before RT on Day 2 of the RT regimen

Drug: XRD-0394; Radiation: Palliative radiotherapy

XRD-0394 (Dose TBD)

EXPERIMENTAL

Subjects will receive a single dose of XRD-0394 capsules approximately 90 minutes before RT. A single biopsy will be performed in each subject (either after RT alone or after XRD-0394 and RT).

Drug: XRD-0394; Radiation: Palliative radiotherapy

Interventions

XRD-0394 DRUG

Single ascending dose

XRD-0394 (Dose TBD); XRD-0394 160 mg; XRD-0394 40 mg; XRD-0394 80 mg

Palliative radiotherapy RADIATION

4 Gy × 5 daily fractions

XRD-0394 (Dose TBD); XRD-0394 160 mg; XRD-0394 40 mg; XRD-0394 80 mg

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed diagnosis of cancer with clear evidence of metastasis on imaging. Subjects with locally advanced or recurrent (non-metastatic) cancer for whom palliative RT is indicated may also be enrolled.
• Scheduled to receive palliative RT delivered as 4 Gray × 5 daily fractions at the discretion of the treating radiation oncologist. The radiation plan should be designed to optimally limit the radiation dose delivered to normal tissues using conformal treatment plans and protocol-specified limits.
• One or more of the following sites of metastasis:
• Skin
• Subcutaneous or soft tissue
• Any other site that will allow the radiation dose to normal structures to remain within protocol-specified dosing limits.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
• Male or female subjects at least 18 years of age who are willing and able to provide written informed consent.
• Other protocol-defined criteria may apply

You may not qualify if:

• Prior radiotherapy to the same region within the last 6 months.
• Subjects who are currently receiving palliative RT for brain metastases. Subjects who have brain metastases may participate in this trial, if they are receiving palliative RT for cancer in a location other than the brain.
• For subjects with cancers involving the spinal cord, the length of the spinal cord requiring palliative treatment must be 10 cm or less.
• Subjects with bone marrow impairment as evidenced by hemoglobin \<8.0 g/dL, neutrophil count \<0.7 × 10\^9/L, or platelets \<80 × 10\^9/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 and/or pacemaker, or impaired cardiovascular function such as New York Heart Association classification \>2.
• Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anticancer therapy within 14 days of first XRD-0394 dose. These treatments should also be held for a minimum of 14 days after completion of RT.
• Subjects receiving bleomycin within 30 days of the first dose of XRD-0394.
• Subjects receiving treatment with any drug that is a strong inhibitor or inducer of cytochrome P450 (CYP) 3A4 enzyme activity or an inhibitor of breast cancer resistance protein (BCRP) within 14 days or 5 half-lives prior to screening (whichever is longer). In particular,
• Glucocorticoids are inducers of CYP3A4. Therefore, dexamethasone, prednisone, or other glucocorticoids should not be administered within 14 days or 5 half-lives prior to screening (whichever is longer) and should only be initiated after the course of palliative RT is complete (and at least 24 hours after the administration of XRD-0394).
• Gefitinib and imatinib are inhibitors of BCRP. Therefore, these agents should not be administered within 14 days or 5 half-lives prior to screening (whichever is longer) and should be held for a minimum of 14 days after completion of RT.
• Participation in another investigational study of an unapproved drug or device or treatment with another ATM, 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.

Sponsors & Collaborators

• XRad Therapeutics Inc: lead

Study Sites (2)

Stanford Clinical Cancer Center

Stanford, California, 94305, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

MeSH Terms

Conditions

Neoplasm Metastasis; Recurrence; Neoplasms

Condition Hierarchy (Ancestors)

Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Disease Attributes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 11, 2021
• First Posted: August 12, 2021
• Study Start: August 24, 2021
• Primary Completion: July 21, 2023
• Study Completion: July 21, 2023
• Last Updated: January 11, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)