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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
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。
Evaluation of PK parameters of Midazolam: Cmax
To evaluate the Cmax of Midazolam administered alone and in combination with HS-10504
Time frame: 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
Time frame: 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
Time frame: 24 hours after administration of Midazolam
Evaluation of PK parameters of Midazolam: Tmax
To evaluate the Tmax of Midazolam administered alone and in combination with HS-10504
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 24 hours after administration of Midazolam
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Evaluation of PK parameters of Midazolam: Vz/F.
To evaluate the Vz/F of Midazolam administered alone and in combination with HS-10504
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: through study completion, an average of 43 days
Pulse
To evaluate the Puls of Midazolam administered alone and in combination with HS-10504.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: through study completion, an average of 43 days
urinalysis
To evaluate the urinalysis of Midazolam administered alone and in combination with HS-10504.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: through study completion, an average of 43 days