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This is a Phase 1, open-label, 2-period fixed sequence design to evaluate the interaction of AZD9291 with omeprazole in approximately 50 healthy, adult male volunteers. Volunteers will receive Treatment A (AZD9291 and omeprazole) in Period 1 and Treatment B (AZD9291 only) in Period 2. The dose of AZD9291 in Period 1 and the dose of AZD9291 in Period 2 will be separated by a washout of at least 21 days (the washout will not be more than 5 weeks). The study will be performed at up to 2 sites in the USA and will assess the effect of omeprazole (proton pump inhibitor) on AZD9291 exposure
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| AZD9291 and omeprazole | Experimental | Sequential treatments of AZD9291 + omeprazole followed by AZD9291 alone, with a washout period in between. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pharmacokinetic sampling - AZD9291 | Procedure | Blood sampling to measure AZD9291 |
| |
| Measure | Description | Time Frame |
|---|---|---|
| AUC of AZD9291 | Area under the plasma concentration-time curve from zero to infinity for AZD9291 | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose |
| Cmax of AZD9291 | Rate and extent of absorption of AZD9291 following single oral doses of AZD9291 tablet formulation by assessment of maximum plasma concentration (Cmax). | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
| Measure | Description | Time Frame |
|---|---|---|
| AUC(0-t) | Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using area under the plasma concentration curve from zero extrapolated to o the time of the last quantifiable concentration, AUC(0-t) | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
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For inclusion in the study volunteers must fulfil the following criteria.
Volunteers must not enter the study if any of the following exclusion criteria are fulfilled:
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| Name | Affiliation | Role |
|---|---|---|
| Serban Ghiorghiu, MSD | AstraZeneca | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Overland Park | Kansas | United States | |||
| Research Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29178442 | Derived | Vishwanathan K, Dickinson PA, Bui K, Cassier PA, Greystoke A, Lisbon E, Moreno V, So K, Thomas K, Weilert D, Yap TA, Plummer R. The Effect of Food or Omeprazole on the Pharmacokinetics of Osimertinib in Patients With Non-Small-Cell Lung Cancer and in Healthy Volunteers. J Clin Pharmacol. 2018 Apr;58(4):474-484. doi: 10.1002/jcph.1035. Epub 2017 Nov 26. |
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136 subjects were enrolled (signed informed consent). Subjects were assigned to treatment if they met all the inclusion and none of the exclusion criteria.
68 subjects were enolled but failed inclusion/exclusion criteria and so were not eligible to be assigned treatment.
The remaining 68 subjects started period 1 and received treatment.
First subject enrolled: 3 September 2014 Last Subject Last Visit: 5 January 2015 Study was performed at 2 sites in the USA.
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| ID | Title | Description |
|---|---|---|
| FG000 | AZD9291 and Omeprazole | Sequential treatments periods of AZD9291 + omeprazole (including a washout) followed by AZD9291 alone. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AZD9291 and Omeprazole Co-administration |
|
| ||||||||||||||||||||||||
| AZD9291 Alone |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | AZD9291 and Omeprazole | Sequential treatments periods of AZD9291 + omeprazole (including a washout) followed by AZD9291 alone. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | AUC of AZD9291 | Area under the plasma concentration-time curve from zero to infinity for AZD9291 | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Geometric Mean | Full Range | nM.h | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose |
|
AEs collected from the day prior to first dose of treatment (omeprazole) until the follow up visit, approximately 3 months.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | AZD9291 and Omeprazole Co-administration | Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cholelithiasis | Hepatobiliary disorders | MedDRA Version 17.1 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA Version 17.1 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Karen So | AstraZeneca | ClinicalTrialTransparency@astrazeneca.com |
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| ID | Term |
|---|---|
| D009369 | Neoplasms |
| D002289 | Carcinoma, Non-Small-Cell Lung |
| ID | Term |
|---|---|
| D002283 | Carcinoma, Bronchogenic |
| D001984 | Bronchial Neoplasms |
| D008175 | Lung Neoplasms |
| D012142 | Respiratory Tract Neoplasms |
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| AZD9291 tablet dosing |
| Drug |
AZD9291 80mg tablet taken on Day 5 in Period 1 and Day 1 in Period 2. |
|
| Omeprazole tablet dosing | Drug | Omeprzole taken from Days 1 to 5 in Period 1. |
|
| Pharmacokinetic sampling - AZ5140 and AZ7550 | Procedure | Blood samples to measure levels of AZ5140 and AZ7550 |
|
| AUC(0-72) | Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using area under the plasma concentration curve from time zero to 72 hours, AUC(0-72) | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72 hours post AZD9291 dose. |
| Tmax | Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using time to reach maximum plasma concentration, tmax | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
| Tlag | Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using lag time before observation of quantifiable analyte concentrations in plasma, tlag | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
| t(1/2) | Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using the terminal half-life, t(1/2) | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
| λz | Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using the terminal rate constant, λz | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
| CL/F of AZD9291 | Assessment of the PK of AZD9291 using the apparent plasma clearance, CL/F | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
| Vz/F of AZD9291 | Assessment of the PK of AZD9291 using the apparent volume of distribution, Vz/F | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
| Cmax of AZ5104 and AZ7550 | Assessment of the PK of AZ5104 and AZ7550 (metabolites to AZD9291) using the maximum plasma concentration, Cmax | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
| AUC of AZ5104 and AZ7550 | Area under the plasma concentration-time curve from zero to infinity of AZ5104 and AZ7550 (metabolites to AZD9291) | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
| Parent to Metabolite Ratios of AZ5104 and AZ7550 Cmax | Assessment of the PK of AZ5104 and AZ7550 Cmax using the parent (AZD9291) to metabolite ratios | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
| Parent to Metabolite Ratios of AZ5104 and AZ7550 AUC | Assessment of the PK of AZ5104 and AZ7550 AUC using the parent (AZD9291) to metabolite ratios | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
| Minneapolis |
| Minnesota |
| United States |
| Withdrawal by Subject |
|
| Protocol non-compliance |
|
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
AZD9291 80 mg single oral dose on Day 1 (Period 2) |
|
|
|
| Primary | Cmax of AZD9291 | Rate and extent of absorption of AZD9291 following single oral doses of AZD9291 tablet formulation by assessment of maximum plasma concentration (Cmax). | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Geometric Mean | Full Range | nM | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
|
|
|
|
| Secondary | AUC(0-t) | Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using area under the plasma concentration curve from zero extrapolated to o the time of the last quantifiable concentration, AUC(0-t) | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Geometric Mean | Full Range | nM.h | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
|
|
|
| Secondary | AUC(0-72) | Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using area under the plasma concentration curve from time zero to 72 hours, AUC(0-72) | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Geometric Mean | Full Range | nM.h | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72 hours post AZD9291 dose. |
|
|
|
| Secondary | Tmax | Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using time to reach maximum plasma concentration, tmax | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Median | Full Range | h | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
|
|
|
| Secondary | Tlag | Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using lag time before observation of quantifiable analyte concentrations in plasma, tlag | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Median | Full Range | h | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
|
|
|
| Secondary | t(1/2) | Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using the terminal half-life, t(1/2) | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Geometric Mean | Full Range | h | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
|
|
|
| Secondary | λz | Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using the terminal rate constant, λz | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Geometric Mean | Full Range | 1/h | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
|
|
|
| Secondary | CL/F of AZD9291 | Assessment of the PK of AZD9291 using the apparent plasma clearance, CL/F | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Geometric Mean | Full Range | L/h | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
|
|
|
| Secondary | Vz/F of AZD9291 | Assessment of the PK of AZD9291 using the apparent volume of distribution, Vz/F | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Geometric Mean | Full Range | L | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
|
|
|
| Secondary | Cmax of AZ5104 and AZ7550 | Assessment of the PK of AZ5104 and AZ7550 (metabolites to AZD9291) using the maximum plasma concentration, Cmax | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Geometric Mean | Full Range | nM | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
|
|
|
|
| Secondary | AUC of AZ5104 and AZ7550 | Area under the plasma concentration-time curve from zero to infinity of AZ5104 and AZ7550 (metabolites to AZD9291) | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Geometric Mean | Full Range | nM.h | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
|
|
|
|
| Secondary | Parent to Metabolite Ratios of AZ5104 and AZ7550 Cmax | Assessment of the PK of AZ5104 and AZ7550 Cmax using the parent (AZD9291) to metabolite ratios | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Geometric Mean | Full Range | Ratio | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
|
|
|
| Secondary | Parent to Metabolite Ratios of AZ5104 and AZ7550 AUC | Assessment of the PK of AZ5104 and AZ7550 AUC using the parent (AZD9291) to metabolite ratios | Pharmacokinetic population - all subjects who received at least 1 dose of AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations or events thought to significantly affect the PK of the investigational product | Posted | Geometric Mean | Full Range | Ratio | PK samples collected in both period 1 and 2 at pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72, 120, 168, 216, 336, and 504 hours post AZD9291 dose. |
|
|
|
| 3 |
| 68 |
| 8 |
| 68 |
| EG001 | AZD9291 Alone | AZD9291 80 mg single oral dose on Day 1 (Period 2) | 0 | 47 | 2 | 47 |
| Blood creatine phosphokinase increased | Investigations | MedDRA Version 17.1 | Non-systematic Assessment |
|
| Transaminases increased | Investigations | MedDRA Version 17.1 | Non-systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA Version 17.1 | Non-systematic Assessment |
|
The Principal Investigator (PI) agrees to collaborate on the contents and formation of any publication and to pay due consideration to comments and opinions offered. AstraZeneca have 30 days for final manuscript review and may require that submission for publication be delayed in order to file patent application.
| D013899 |
| Thoracic Neoplasms |
| D009371 | Neoplasms by Site |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| AZ7550 |
|
| AZ7550 |
|
| AZ7550 |
|
| AZ7550 |
|
| AZ7550 |
|
| AZ7550 |
|
| Geomteric mean ratio |
| 89.70 |
| 2-Sided |
| 90 |
| 83.89 |
| 95.91 |
| Yes |
| Non-Inferiority or Equivalence |
90% CIs of geometric mean ratios being within 80% to 125% |
AZ7550 |
| Geometric mean ratio |
| 94.03 |
| 2-Sided |
| 90 |
| 89.92 |
| 98.33 |
| Yes |
| Non-Inferiority or Equivalence |
90% CIs of geometric mean ratios being within 80% to 125% |