Assessing the Safety, Tolerability and Pharmacokinetics(PK) of DZD9008 and the Effect of Low-fat Meal on PK of DZD9008 in Healthy Adult Participants

Study Overview
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Brief Summary
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This is a Phase 1, randomised, double-blind, placebo-controlled, single ascending dose sequential group study in healthy participants. This study consists of three parts: Part A (single dose escalation, SAD) , Part B (food effect, FE) and Part C (relative bioavailability, BA).

Official Title
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A Phase 1 Randomised, Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of DZD9008 Following Single Ascending Dose and the Effect of Low-fat Meal on Pharmacokinetics of DZD9008 in Healthy Adult Participants

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: DZD9008
* Drug: Placebo
* Drug: DZD9008
* Drug: DZD9008


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be able to understand the nature of the trial and provide a signed and dated, written informed consent form before any study-specific procedures, sampling and analyses. Provision of signed and dated written Optional Genetic Research informed consent prior to collection of samples for optional genetic research. Healthy male or female participants aged 18 to 60 years (inclusive), with BMI 18.0 to 30.0 kg/m2 (inclusive). Body weight: ≥ 55 kg for male, ≥ 45 kg for female. Healthy participants defined as the absence of acute or chronic clinically significant deviations from normal in medical history, physical examination, visual assessment, electrocardiogram (ECG), and clinical laboratory determinations at screening. Participants must agree to practice effective contraception. Normal baseline PFTs (≥ 80% predicted normal for spirometry, lung volumes). Normal baseline ECG (QTcF < 450 msec, PR < 210 msec). Non-smoker (not smoked within 3 months). Liver biochemistry parameters: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN); Total bilirubin ≤ 1.5 × ULN Adequate organ function including hepatic, renal, cardiac, visual and bone marrow function as determined by the investigator. Exclusion Criteria: Ongoing or prior pulmonary disease including asthma, chronic obstructive pulmonary disease, interstitial lung disease and pneumonitis including but not limited to drug-related pneumonitis. Women who are breast feeding. Positive pregnancy test prior to study entry. History of malignancy of any type, with the exception of the following: surgically excised non-melanomatous skin cancers more than 5 years prior to receiving IP. A history of additional risk factors for TdP (e.g. heart failure, hypokalemia, family history of Long QT syndrome). No prior history of atrial fibrillation within 6 months prior to first dosing of DZD9008 Manifestations of malabsorption due to prior GI surgery, GI disease, or for an unknown other reason that may affect the absorption of DZD9008-. Pulmonary infections or other active infection within 30 days of informed consent History of bleeding disorder (including hemophilia, Von Willebrand disease, etc), history of stroke or intracranial haemorrhage within 6 months before study drug administration. Judgement by the investigator that the participant is not likely to comply with study procedures, restrictions and requirements. Positive serology or a known history of hepatitis B virus (HBV), hepatitis C virus (HCV), HIV. Resting blood pressure > 140/90 mmHg at screening . Resting pulse rate < 45 beats per minute. History of severe allergy or hypersensitivity reaction or ongoing allergy or hypersensitivity reaction, as judged by investigator, or history of hypersensitivity to EGFR/HER2/BTK inhibitors.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single oral dose of DZD9008<br>single dose of DZD9008 (50 mg, 100 mg, 200 mg, 300 mg and 400 mg, tablet) | Drug: DZD9008<br>* In the double blind, randomised, placebo-controlled trial (Part A - SAD), healthy adult participants will be randomized to receive DZD9008 at different dose levels. There are 5 planned dose cohorts, starting from 50 mg once daily. If tolerated, subsequent cohorts will test increasing doses of DZD9008 or matching placebo, namely 100 mg, 200 mg, 300 mg and 400 mg.<br>|
| Placebo Comparator: single oral dose of placebo<br>single dose of placebo (matching placebo, 50 mg, 100 mg, 200 mg, 300 mg and 400 mg, tablet) | Drug: Placebo<br>* In the double blind, randomised, placebo-controlled trial (Part A - SAD), healthy adult participants will be randomized to receive matching placebo for DZD9008 at different dose levels. There are 5 planned dose cohorts of matching placebo for DZD9008, starting from 50 mg once daily.<br>|
| Experimental: single oral dose of DZD9008 (300 mg, tablet)<br> | Drug: DZD9008<br>* Healthy adult participants will be randomized to receive DZD9008 single dose at a defined dose under a cross-over condition with or without food (low-fat in Part B; high-fat in Part D).<br>|
| Experimental: single oral dose of DZD9008 (100 mg, tablet or suspension)<br> | Drug: DZD9008<br>* In Part C, healthy adult participants will be enrolled to receive a single dose of DZD9008 as suspension in period 1 and as tablet in period 2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants that experience Adverse Events (AEs) and Serious Adverse Events (SAEs) | To assess the safety and tolerability of DZD9008 following oral administration of single ascending doses in healthy adult participants. | up to 14 days after study drug administration | 
| Number of participants with clinically significant laboratory assessment abnormalities | To assess the safety and tolerability of DZD9008 following oral administration of single ascending doses in healthy adult participants. | up to 14 days after study drug administration | 
| Number of participants with clinically significant 12-lead electrocardiograms (ECGs) abnormalities | To assess the safety and tolerability of DZD9008 following oral administration of single ascending doses in healthy adult participants. | up to 14 days after study drug administration | 
| Number of participants with clinically significant abnormalities in LVEF | To assess the safety and tolerability of DZD9008 following oral administration of single ascending doses in healthy adult participants. | up to 14 days after study drug administration | 
| Number of participants with clinically significant abnormalities in FEV1% | To assess the safety and tolerability of DZD9008 following oral administration of single ascending doses in healthy adult participants. | up to 14 days after study drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of DZD9008 |  | up to 10 days after study drug administration | 
| Time to reach maximum plasma concentration (tmax) |  | up to 10 days after study drug administration | 
| Area under the concentration-time curve from time 0 (pre-dose) to the time of the dosing interval (AUC0-t) |  | up to 10 days after study drug administration | 
| Area under the concentration-time curve from time 0 to infinity (AUC0-inf) |  | up to 10 days after study drug administration | 
| Apparent total plasma clearance (CL/F) |  | up to 10 days after study drug administration | 
| Apparent volume of distribution (Vz/F) |  | up to 10 days after study drug administration | 
| Mean residence time (MRT) |  | up to 10 days after study drug administration | 
| Terminal elimination half-life (t1/2) |  | up to 10 days after study drug administration |