An Open-label, Fixed-sequence Phase I Clinical Trial to Evaluate the Effect of HS-10504 on the Pharmacokinetics of Midazolam in Patients With Non-small Cell Lung Cancer

An Open-label, Fixed-sequence Phase I Clinical Trial to Evaluate the Effect of HS-10504 on the Pharmacokinetics of Midazolam in Patients With Non-small Cell Lung Cancer

This is an open-label, fixed-sequence Phase I clinical trial to evaluate the effect of HS-10504 on the pharmacokinetics of midazolam (CYP3A4 substrate) in patients with EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) who have experienced disease progression during or after treatment with EGFR-TKIs.

This study consists of two stages: Stage 1 (DDI evaluation period, C0D1 to C2D21) and Stage 2 (drug donation period, from C3D1 onward). Each cycle contains 21 days, except for Cycle 0.

Stage 1 (DDI evaluation period, C0D1 to C2D21): Enrolled participants receive a single oral dose of midazolam oral solution 1 mg (2 mg/mL, 0.5 mL) on C0D1 and C2D20, respectively; and receive HS-10504 tablets 400 mg (100 mg/tablet, 4 tablets) once daily from C1D1 to C2D21.

Stage 2 (drug donation period, from C3D1 onward): After completing Stage 1, participants may decide, based on the investigator's judgment and their own willingness, whether to enter Stage 2 (the extended drug donation period, which is optional and not mandatory). This stage continues until the participant voluntarily requests discontinuation, is lost to follow-up, experiences disease progression, develops intolerable toxicity, is judged by the investigator to no longer derive benefit from the treatment, or the drug has been approved for marketing, whichever occurs first.

Inclusion Criteria:

1. Histologically or cytologically confirmed locally advanced or metastatic NSCLC
2. Disease progression or intolerance to prior third-generation EGFR TKI therapy in patients with mNSCLC
3. Confirmed EGFR mutation positivity in participants before enrollment.
4. At least one target lesion according to RECIST 1.1
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 with no deterioration in the 2 weeks prior to the first dose
6. Minimum life expectancy greater than 12 weeks
7. Female participants of childbearing potential must agree to use appropriate contraception (refer to section 12.5) from the time of signing informed consent until 6 months after the last dose, and should not breastfeed; male participants must agree to use barrier contraception (i.e., condoms) from the time of signing informed consent until 6 months after the last dose
8. Willing to participate in this clinical trial, understand the study procedures, and be able to provide written informed consent.

Exclusion Criteria:

1. Has received or is currently receiving the following treatments:

   1. Prior or current treatment with a fourth-generation EGFR tyrosine kinase inhibitor.
   2. Use of strong/moderate inhibitors or strong/moderate inducers of CYP3A4, CYP3A5, CYP2C8, and/or CYP2D6, or narrow therapeutic index drugs that are sensitive substrates of CYP3A4, CYP3A5, P-gp, and BCRP within 14 days or 5 half-lives (whichever is longer) prior to the first dose of investigational product; or need to continue these medications during the study period.
   3. Use of drugs that affect gastric acid secretion or intragastric pH within 7 days prior to the first dose of investigational product.
   4. Currently receiving treatment with drugs known to prolong the QT interval or that may cause torsade de pointes; or need to continue these medications during the study period

2. Presence of toxicities from prior anti-tumor therapy that have not resolved to < Grade 2 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

3. History of other primary malignancies.

4. Inadequate bone marrow reserve or hepatic/renal organ function.

5. Meets any of the following cardiac criteria:

   1. Mean Fridericia-corrected QT interval (QTcF) > 470 msec on resting electrocardiogram (ECG);
   2. Resting ECG shows any clinically significant rhythm, conduction, or ECG morphological abnormality deemed important by the investigator (e.g., complete left bundle branch block, third-degree atrioventricular block, second-degree atrioventricular block, and PR interval > 250 msec, etc.);
   3. Presence of any factors that increase the risk of QT prolongation or arrhythmic events, such as heart failure, refractory hypokalemia, congenital long QT syndrome, family history of long QT syndrome, unexplained sudden death in a first-degree relative under 40 years of age, or any concomitant medication that prolongs the QT interval;
   4. Left ventricular ejection fraction (LVEF) < 50%.

6. Severe, uncontrolled, or active cardiovascular disease.

7. Severe or poorly controlled diabetes mellitus.

8. Severe or poorly controlled hypertension.

9. Clinically significant bleeding symptoms or obvious bleeding tendency within 1 month prior to the first dose.

10. Severe arterial thrombotic event within 3 months prior to the first dose.

11. Severe infection within 4 weeks prior to the first dose.

12. Continuous corticosteroid therapy for more than 30 days within 30 days prior to the first dose, or need for long-term corticosteroid therapy, or other acquired or congenital immunodeficiency diseases, or history of organ transplantation

13. Known active infectious disease.

14. Clinically severe gastrointestinal abnormalities that may affect drug intake, transport, or absorption.

15. Hepatic encephalopathy, hepatorenal syndrome, or ≥C (incomplete in original).

16. Other moderate to severe pulmonary diseases that seriously impair respiratory function and may interfere with the detection or management of drug-related pulmonary toxicity.

17. Previous history of severe neurological or psychiatric disorders.

18. Female participants who are pregnant, breastfeeding, or planning to become pregnant during the study period.

19. History of severe allergies, or hypersensitivity to any component of HS-10504 tablets or midazolam oral solution, or history of hypersensitivity to drugs with a similar chemical structure or of the same class as HS-10504.

20. History of ventilation difficulty or severe airway obstruction.

21. Any severe or uncontrolled ocular condition that, in the physician's judgment, may increase the patient's risk; or ocular abnormalities requiring surgery or expected to require surgical treatment during the study period.

22. Participants who, in the investigator's judgment, may have poor compliance with study procedures and requirements.

23. In the investigator's judgment, presence of any life-threatening complication.