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Trial of XRD-0394, a Kinase Inhibitor, in Combination With Palliative Radiotherapy in Advanced Cancer Patients
Trial ID: NCT05002140
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.
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
- 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:
- 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
- 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.
radiation: Palliative radiotherapy
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