A Phase I, Open-label Study to Assess Bioavailability of a Single Oral Dose of AZD9291 vs an IV Dose of [14C]AZD9291

Study Overview
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Brief Summary
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The Sponsor is developing the study drug, AZD9291, for the potential treatment of nonsmall cell lung cancer. Lung cancer has been the most common cancer in the world for several decades and represents 12.8% of all new cancer cases in 2008. The purpose of this study is to see how much AZD9291 is taken up by the body when dosed by mouth (tablet) compared to when the study drug is dosed once by injection directly into the vein (intravenously). The dose given directly into the vein will be radiolabelled. This means that the test drug has a radioactive component which helps us to track where the drug is in the body. This allows us to detect the differences between the tablet and the intravenous dose. The study will be performed in 12 healthy male subjects aged 18-65 years. On Day 1, subjects will be dosed with a single oral dose of 80 milligrams AZD9291 tablet followed by 100 micrograms [14C] AZD9291 dosed as an intravenous microdose beginning 5 hours and 45 minutes after the oral dose has been administered. Subjects will remain in the study centre until after the 120 hour post-dose blood sample is obtained and will return to the clinic for further visits on Day 8, 10, 15 and 22 for pharmacokinetic and safety assessments.

Detailed Description
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The study is a Phase I, open label, single dose, single centre study performed in 12 healthy male subjects aged 18 to 65 years, inclusive. This study will assess the absolute bioavailability of AZD9291 and evaluate the PK parameters following a single oral dose of AZD9291 and a radiolabelled IV microdose of AZD9291 in healthy male subjects. Oral AZD9291and [14C] AZD9291 intravenous solution are referred to as the investigational products in this study. A screening visit (Visit 1) to assess the eligibility of the healthy male subjects will occur within 28 days of the administration of the investigational product. Screening assessments will include evaluation of opthalmological assessments, clinical chemistry, haematology, urinalysis, a physical examination, vital signs, 12-lead electrocardiograms (ECGs), medical and surgical history, screening for drugs of abuse, alcohol, hepatitis B and C, and HIV, and recording of concomitant medications and Adverse Events. Study related procedures will only be performed after signing of the Informed Consent Form. The healthy male subjects will be admitted to the study centre the day before administration of the investigational product (Day 1; Visit 2). On Day 1 (Visit 2), subjects will be dosed with a single oral dose of 80 mg AZD9291 tablet followed by 100 μg [14C] AZD9291 dosed as an IV microdose beginning 5 hours and 45 minutes after the oral dose has been administered. The IV microdose will be infused over 15 minutes and the end of the infusion will be co incidental with median oral tmax (ie, estimated tmax is 6 hours). The subjects will remain in the study centre until the 120 hour post dose PK blood sample is obtained. Ambulatory visits will occur on Days 8 (Visit 3), 10 (Visit 4), 15 (Visit 5) and 22 (Visit 6) for PK and safety assessments. A follow up visit (Visit 7) will occur 21 to 28 days after discharge (Days 27 - 34) from the study centre and will include routine safety assessments.

Official Title
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A Phase I, Open-label, Single Dose, Single-Centre Study to Assess the Absolute Bioavailability of a Single Oral Dose of AZD9291 With Respect to an Intravenous Microdose of [14C]AZD9291 in Healthy Male Subjects

Conditions
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Oncology

Intervention / Treatment
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* Drug: AZD9291
* Drug: [14C]AZD9291


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed dated, written informed consent. Healthy male aged 18 to 65 yrs with suitable veins for blood sampling BMI: 19 and 32 kg/m2 inclusive, weight at least 50 kg and no more than 100 kg, inclusive. At screening, calculated creatinine clearance ≥50 mL/min using Cockcroft Gault formula. Willing to use defined methods of contraception Willing and able to comply with study procedures, restrictions and requirements. Provision of informed consent for genetic research. Declining genetic research will not exclude subjects from other aspects of study. Exclusion Criteria: Involvement in planning and/or conduct of study. Subjects previously enrolled in this study. History of clinically significant disease or disorder which, either puts subject at risk because of participation in study, or influences results or subject's ability to participate in study. History or presence of condition known to interfere with ADME of drugs. Any clinically significant abnormalities in physical examination, as judged by PI. Acute illness, surgical procedures, or trauma from within 2 wks before screening until first admin of investigational product (IMP). Subjects who have received live or live-attenuated vaccine in 2 wks prior to IMP admin. Subjects with active malignancy or neoplastic disease in previous 12 mths. A suspected/manifested infection according to IATA Categories A and B. Positive screening tests for serum hepatitis B surface antigen, hepatitis C antibody, or HIV. Any clinically important abnormalities in rhythm, conduction, or morphology of resting 12-lead ECG, QT interval >470 ms. Known or suspected history of significant drug abuse. Positive screen for drugs of abuse or cotinine at screening or positive screen for alcohol, drugs of abuse, or cotinine on admission to centre prior to first admin of IMP. History of alcohol abuse or excessive intake of alcohol, defined as regular weekly intake of more than 21 units of alcohol in men History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by PI, or history of hypersensitivity to AZD9291, its excipients, or drugs with a similar chemical structure or class. Use of any prescribed or non-prescribed medication, including drugs during the 4 wks (or longer depending on the medication's half-life) prior to admin of AZD9291 is not permitted. Occasional use of paracetamol and adrenergic nasal spray for relief of nasal congestion is permitted at the discretion of the PI. Exceptions as agreed by PI and sponsor's medical monitor if do not interfere with aims of study. Use of drugs with enzyme inducing properties such as St John's Wort within 4 wks prior to IMP administration. Any intake of grapefruit, grapefruit juice, Seville oranges or products containing these fruit within 7 days of first admin of IMP. Blood donation within 1 mth of screening or any blood donation/blood loss greater than 500 mL during 3 mths prior to screening. Subjects who received another NCE or participated in any other clinical study (including methodology studies where no drugs were given) within 3 mths of first admin of IMP Judgment by PI that subject should not participate in study if subject is considered unlikely to comply with study procedures, restrictions, and requirements. Ongoing or planned inpatient surgery, dental procedure, or hospitalisation during study Radiation exposure exceeding 5 mSv in last 12 mths or 10 mSv in last 5 yrs. Admin of any amount of a [14C]-labelled compound within last 12 mths. Used of nicotine products (including cigarettes) within previous 3 mths. Judgment by PI that subject would not be able to understand or cooperate with requirements of study. Previous bone marrow transplant Blood transfusion within 120 days of genetic sample collection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bioavailability of AZD9291<br>To assess the absolute bioavailability of a single oral dose of AZD9291 with respect to an intravenous microdose of [14C]AZD9291 | Drug: AZD9291<br>* Single oral dose of 80 mg AZD9291 tablet on Day 1 administered orally with 240 mL water following an overnight fast.<br>Drug: [14C]AZD9291<br>* Each healthy male subject will also receive a single, radiolabeled, 100 μg dose of [14C] AZD9291 administered as an IV microdose infusion starting at 5 hours and 45 minutes after receiving the oral dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Oral Bioavailability | Absolute bioavailability of AZD9291 will be calculated from area under the plasma concentration versus time curve (AUC) of the oral dose of AZD9291 / AUC of the IV dose of [14C]AZD9291 x IV dose/Oral dose x 100 | Samples taken at pre-dose, 1, 2, 3, 4, 5:45, 5:52, 6, 6:05, 6:10, 6:20, 6:25, 6:30, 7, 8, 9, 10, 12, 14, 16, 18, 24, 30, 48, 72, 120, 168, 216, 336 and 504 hours relative to the oral dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC for AZD9291 and it's Metabolites AZ5104 and AZ7550 | Pharmacokinetic (PK) profile of the oral dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from zero to infinity for AZD9291 and it's metabolites AZ5104 and AZ7550. | Samples taken at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336 and 504 hours post-dose. | 
| AUC(0-24) for AZD9291 and it's Metabolites AZ5104 and AZ7550 | Pharmacokinetic (PK) profile of the oral dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from time zero to 24 hours (AUC 0-24) for AZD9291 and it's metabolites AZ5104 and AZ7550. | Samples taken at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336 and 504 hours post-dose. | 
| AUC(0-120) for AZD9291 and it's Metabolites AZ5104 and AZ7550 | Pharmacokinetic (PK) profile of the oral dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from time zero to 120 hours (AUC 0-120) for AZD9291 and it's metabolites AZ5104 and AZ7550. | Samples taken at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336 and 504 hours post-dose. | 
| AUC(0-t) for AZD9291 and it's Metabolites AZ5104 and AZ7550 | Pharmacokinetic (PK) profile of the oral dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from time zero to the last quantifiable concentration (AUC 0-t) for AZD9291 and it's metabolites AZ5104 and AZ7550. | Samples taken at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336 and 504 hours post-dose. | 
| Cmax for AZD9291 and it's Metabolites AZ5104 and AZ7550 | PK profile of the oral dose of AZD9291 in terms of the maximum observed plasma concentration (Cmax) for AZD9291 and it's metabolites AZ5104 and AZ7550. | Samples taken at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336 and 504 hours post-dose. | 
| Tmax for AZD9291 and it's Metabolites AZ5104 and AZ7550 | PK profile of the oral dose of AZD9291 in terms of the time to maximum observed plasma concentration (Tmax) for AZD9291 and it's metabolites AZ5104 and AZ7550. | Samples taken at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336 and 504 hours post-dose. | 
| t1/2,λz for AZD9291 and it's Metabolites AZ5104 and AZ7550 | PK profile of the oral dose of AZD9291 in terms of the elimination half life (t1/2,λz) for AZD9291 and it's metabolites AZ5104 and AZ7550. | Samples taken at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336 and 504 hours post-dose. | 
| CL/F for AZD9291 | PK profile of the oral dose of AZD9291 in terms of apparent total body clearance of drug from plasma after extravascular administration(CL/F) for AZD9291. | Samples taken at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336 and 504 hours post-dose. | 
| AUC for [14C]AZD9291 and it's Metabolites [14C]AZ5104 and [14C]AZ7550 | Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from zero to infinity for [14C]AZD9291 and it's metabolites [14C]AZ5104 and [14C]AZ7550. | Samples taken pre-dose, during the infusion, immediately at the end of infusion and then at 5, 10, 20, 25 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 42, 66, 114, 162, 210, 330 and 498 hours after the end of the infusion. | 
| AUC(0-24) for [14C]AZD9291 and it's Metabolites [14C]AZ5104 and [14C]AZ7550 | Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from time zero to 24 hours (AUC 0-24) for [14C]AZD9291 and it's metabolites [14C]AZ5104 and [14C]AZ7550. | Samples taken pre-dose, during the infusion, immediately at the end of infusion and then at 5, 10, 20, 25 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 42, 66, 114, 162, 210, 330 and 498 hours after the end of the infusion. | 
| AUC(0-120) for [14C]AZD9291 and it's Metabolites [14C]AZ5104 and [14C]AZ7550 | Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from time zero to 120 hours (AUC 0-120) for [14C]AZD9291 and it's metabolites [14C]AZ5104 and [14C]AZ7550. | Samples taken pre-dose, during the infusion, immediately at the end of infusion and then at 5, 10, 20, 25 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 42, 66, 114, 162, 210, 330 and 498 hours after the end of the infusion. | 
| AUC(0-t) for [14C]AZD9291 and it's Metabolites [14C]AZ5104 and [14C]AZ7550 | Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of Area under the plasma concentration - time curve (AUC) from time zero to the last quantifiable concentration (AUC 0-t) for [14C]AZD9291 and it's metabolites [14C]AZ5104 and [14C]AZ7550. | Samples taken pre-dose, during the infusion, immediately at the end of infusion and then at 5, 10, 20, 25 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 42, 66, 114, 162, 210, 330 and 498 hours after the end of the infusion. | 
| Cmax for [14C]AZD9291 and it's Metabolites [14C]AZ5104 and [14C]AZ7550 | Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of the maximum observed plasma concentration (Cmax) for [14C]AZD9291 and it's metabolites [14C]AZ5104 and [14C]AZ7550. | Samples taken pre-dose, during the infusion, immediately at the end of infusion and then at 5, 10, 20, 25 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 42, 66, 114, 162, 210, 330 and 498 hours after the end of the infusion. | 
| Tmax for [14C]AZD9291 and it's Metabolites [14C]AZ5104 and [14C]AZ7550 | Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of the the time to maximum observed plasma concentration (Tmax) for [14C]AZD9291 and it's metabolites [14C]AZ5104 and [14C]AZ7550. | Samples taken pre-dose, during the infusion, immediately at the end of infusion and then at 5, 10, 20, 25 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 42, 66, 114, 162, 210, 330 and 498 hours after the end of the infusion. | 
| t1/2,λz for [14C]AZD9291 and it's Metabolites [14C]AZ5104 and [14C]AZ7550 | Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of the elimination half life (t1/2,λz) for [14C]AZD9291 and it's metabolites [14C]AZ5104 and [14C]AZ7550. | Samples taken pre-dose, during the infusion, immediately at the end of infusion and then at 5, 10, 20, 25 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 42, 66, 114, 162, 210, 330 and 498 hours after the end of the infusion. | 
| CL for [14C]AZD9291 | Pharmacokinetic (PK) profile of the IV dose of AZD9291 in terms of total body clearance of drug from plasma after intravascular administration (CL) for [14C]AZD9291. | Samples taken pre-dose, during the infusion, immediately at the end of infusion and then at 5, 10, 20, 25 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 42, 66, 114, 162, 210, 330 and 498 hours after the end of the infusion. |