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.

Study Overview

• Status: Not yet recruiting
• Conditions: NSCLC
• Intervention / Treatment: Drug: HS-10504； midazolam

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group; Drug-drug interaction Arm	Drug: HS-10504； midazolam; HS-10504：Participants receive HS-10504 tablets 400 mg (100 mg/tablet, 4 tablets) once daily Midazolam：Participants receive a single oral dose of midazolam oral solution 1 mg (2 mg/mL, 0.5 mL) on C0D1 and C2D20, respectively。

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of PK parameters of Midazolam: Cmax	To evaluate the Cmax of Midazolam administered alone and in combination with HS-10504	24 hours after administration of Midazolam
Evaluation of PK parameters of Midazolam: AUC0-t	To evaluate the AUC0-t of Midazolam administered alone and in combination with HS-10504	24 hours after administration of Midazolam
Evaluation of PK parameters of Midazolam: AUC0-∞	To evaluate the AUC0-∞ of Midazolam administered alone and in combination with HS-10504	24 hours after administration of Midazolam

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of PK parameters of Midazolam: Tmax	To evaluate the Tmax of Midazolam administered alone and in combination with HS-10504	24 hours after administration of Midazolam
Evaluation of PK parameters of Midazolam: t1/2z	To evaluate the t1/2z of Midazolam administered alone and in combination with HS-10504	24 hours after administration of Midazolam
Evaluation of PK parameters of Midazolam: λz	To evaluate the λz of Midazolam administered alone and in combination with HS-10504	24 hours after administration of Midazolam
Evaluation of PK parameters of Midazolam: CLz/F	To evaluate the CLz/F of Midazolam administered alone and in combination with HS-10504	24 hours after administration of Midazolam
Evaluation of PK parameters of Midazolam: Vz/F.	To evaluate the Vz/F of Midazolam administered alone and in combination with HS-10504	24 hours after administration of Midazolam
Evaluation of PK parameters of 1-OH Midazolam: Cmax	To evaluate the Cmax of 1-OH Midazolam administered alone and in combination with HS-10504	24 hours after administration of Midazolam
Evaluation of PK parameters of 1-OH Midazolam: AUC0-t	To evaluate the AUC0-t of 1-OH Midazolam administered alone and in combination with HS-10504	24 hours after administration of Midazolam
Evaluation of PK parameters of 1-OH Midazolam: AUC0-∞	To evaluate the AUC0-∞ of 1-OH Midazolam administered alone and in combination with HS-10504	24 hours after administration of Midazolam
Evaluation of PK parameters of 1-OH Midazolam: Tmax	To evaluate the Tmax of 1-OH Midazolam administered alone and in combination with HS-10504	24 hours after administration of Midazolam
Evaluation of PK parameters of 1-OH Midazolam: t1/2z.	To evaluate the t1/2z of 1-OH Midazolam administered alone and in combination with HS-10504	24 hours after administration of Midazolam
Evaluation of PK parameters of HS-10504 and metabolite M6-2: Cmin	To evaluate the Cmin of HS-10504 and metabolite M6-2	24 hours after administration of HS-10504
Evaluation of PK parameters of HS-10504 and metabolite M6-2: Cmax	To evaluate the Cmax of HS-10504 and metabolite M6-2	24 hours after administration of HS-10504
Evaluation of PK parameters of HS-10504 and metabolite M6-2: AUC0-24 h	To evaluate the AUC0-24 h of HS-10504 and metabolite M6-2	24 hours after administration of HS-10504
Evaluation of PK parameters of HS-10504 and metabolite M6-2: Tmax.	To evaluate the Tmax of HS-10504 and metabolite M6-2	24 hours after administration of HS-10504
Adverse events	To evaluate the adverse events (AEs) of Midazolam administered alone and in combination with HS-10504.	through study completion, an average of 43 days
blood pressure	To evaluate the blood pressure of Midazolam administered alone and in combination with HS-10504.	through study completion, an average of 43 days
Pulse	To evaluate the Puls of Midazolam administered alone and in combination with HS-10504.	through study completion, an average of 43 days
body temperature	To evaluate the body temperature of Midazolam administered alone and in combination with HS-10504.	through study completion, an average of 43 days
respiratory rate	To evaluate the respiratory rate of Midazolam administered alone and in combination with HS-10504.	through study completion, an average of 43 days
complete blood count (CBC)	To evaluate the complete blood count (CBC) of Midazolam administered alone and in combination with HS-10504.	through study completion, an average of 43 days
urinalysis	To evaluate the urinalysis of Midazolam administered alone and in combination with HS-10504.	through study completion, an average of 43 days
blood chemistry	To evaluate the blood chemistry of Midazolam administered alone and in combination with HS-10504.	through study completion, an average of 43 days
coagulation tests	To evaluate the coagulation tests of Midazolam administered alone and in combination with HS-10504.	through study completion, an average of 43 days
12-lead electrocardiogram（heart rate）	To evaluate the 12-lead electrocardiogram（heart rate） of Midazolam administered alone and in combination with HS-10504	through study completion, an average of 43 days
12-lead electrocardiogram（PR）	To evaluate the 12-lead electrocardiogram（PR） of Midazolam administered alone and in combination with HS-10504	through study completion, an average of 43 days
12-lead electrocardiogram（RR）	To evaluate the 12-lead electrocardiogram（RR） of Midazolam administered alone and in combination with HS-10504	through study completion, an average of 43 days
12-lead electrocardiogram（QRS duration）	To evaluate the 12-lead electrocardiogram（QRS duration） of Midazolam administered alone and in combination with HS-10504	through study completion, an average of 43 days
12-lead electrocardiogram（QTcF）	To evaluate the 12-lead electrocardiogram（QTcF） of Midazolam administered alone and in combination with HS-10504	through study completion, an average of 43 days
physical examination of Midazolam administered alone and in combination with HS-10504.	To evaluate the abnormal of the physical examination（1) Eyes; 2) Ear, nose, throat; 3) Cardiovascular system; 4) Chest and respiratory system; 5) Abdominal examination; 6) Skin and mucous membranes; 7) Spine and limbs; 8) Musculoskeletal system; 9) Nervous system; 10) Lymph nodes; 11) Genitourinary system; 12) Others.） of Midazolam administered alone and in combination with HS-10504.	through study completion, an average of 43 days

Collaborators and Investigators

• Sponsor: Jiangsu Hansoh Pharmaceutical Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Estimated): June 27, 2026
• Primary Completion (Estimated): November 19, 2026
• Study Completion (Estimated): July 20, 2027

Study Registration Dates

• First Submitted: June 1, 2026
• First Submitted That Met QC Criteria: June 29, 2026
• First Posted (Actual): July 6, 2026

Study Record Updates

• Last Update Posted (Actual): July 6, 2026
• Last Update Submitted That Met QC Criteria: June 29, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: NSCLC; Phase I; Drug interaction; HS-10504
• Other Study ID Numbers: HS-10504-113

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No