Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Gastrointestinal Agents

Amino Acids

Osimertinib

Omeprazole

Antacids

Anti-Ulcer Agents

Proton Pump Inhibitors

Enzyme Inhibitors

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

Sequential treatments of AZD9291 + omeprazole followed by AZD9291 alone, with a washout period in between.

Pharmacokinetic sampling - AZD9291

AZD9291 80mg tablet taken on Day 5 in Period 1 and Day 1 in Period 2.

AZD9291 tablet dosing

Omeprzole taken from Days 1 to 5 in Period 1.

Omeprazole tablet dosing

Blood samples to measure levels of AZ5140 and AZ7550

Pharmacokinetic sampling - AZ5140 and AZ7550

Serban Ghiorghiu, MSD

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

Drug-Drug Interaction Study With AZD9291 and Omeprazole in Healthy Volunteers

A Phase I, Fixed Sequence, Open-label, Study to Assess the Pharmacokinetics of AZD9291 in Healthy Male Volunteers When a Single Oral Dose of AZD9291 80 mg is Administered Alone and in Combination With Omeprazole

Area under the plasma concentration-time curve from zero to infinity for AZD9291

Rate and extent of absorption of AZD9291 following single oral doses of AZD9291 tablet formulation by assessment of maximum plasma concentration (Cmax).

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)

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)

Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using time to reach maximum plasma concentration, tmax

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

Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using the terminal half-life, t(1/2)

Assessment of the PK of AZD9291 (parent compound), AZ5104 (metabolite) and AZ7550 (metabolite) using the terminal rate constant, λz

Assessment of the PK of AZD9291 using the apparent plasma clearance, CL/F

Assessment of the PK of AZD9291 using the apparent volume of distribution, Vz/F

Assessment of the PK of AZ5104 and AZ7550 (metabolites to AZD9291) using the maximum plasma concentration, Cmax

Area under the plasma concentration-time curve from zero to infinity of AZ5104 and AZ7550 (metabolites to AZD9291)

Assessment of the PK of AZ5104 and AZ7550 Cmax using the parent (AZD9291) to metabolite ratios

Assessment of the PK of AZ5104 and AZ7550 AUC using the parent (AZD9291) to metabolite ratios

AstraZeneca

Once daily dosing of omeprazole 40 mg on Days 1 to 5 and AZD9291 80 mg single oral dose on Day 5 (Period 1).

AZD9291 and Omeprazole Co-administration

AZD9291 80 mg single oral dose on Day 1 (Period 2)

AZD9291 Alone

Sequential treatments periods of AZD9291 + omeprazole (including a washout) followed by AZD9291 alone.

AZD9291 and Omeprazole

Age, Continuous

Sex: Female, Male

Dr Karen So

Study sized so experiment-wise power for the 90% CIs of geometric mean ratios for both AUC and Cmax of AZD9291 being within 80% to 125% was 90% (95% for each parameter). Within subject CV assumed to be 23%. 5% change in exposure also assumed.

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

AUC of AZD9291

Cmax of AZD9291

AZD9291

AZ5104

AZ7550

AUC(0-t)

AUC(0-72)

Tmax

Tlag

t(1/2)

CL/F of AZD9291

Vz/F of AZD9291

Cmax of AZ5104 and AZ7550

AZ7750

AUC of AZ5104 and AZ7550

Parent to Metabolite Ratios of AZ5104 and AZ7550 Cmax

Parent to Metabolite Ratios of AZ5104 and AZ7550 AUC

Hematinics

Liver Extracts

Patients without a history or presence of hepatic disease

Patients defined by the Child-Pugh classification system to be Child-Pugh A

Patients defined by the Child-Pugh classification system to be Child-Pugh B

Part A - single 80mg oral dose AZD9291 (administered as 1 80mg tablet). Part B - 80mg oral dose AZD9291 od.

Blood sampling to measure AZD9291 pharmacokinetic parameters.

Blood samples to measure the pharmacokinetic parameters of AZ5104 and AZ7550.

Yuri Rukazenkov

This is a 2-part study in patients with advanced solid tumours. Part A will investigate the pharmacokinetics (PK) of AZD9291 in patients with mild or moderate hepatic impairment compared to patients with normal hepatic function; Part B will allow any patient with mild or moderate hepatic impairment or normal hepatic function, who completes Part A, continued access to AZD9291 after the PK phase and will provide additional safety data.

Study to Assess the Blood Levels and Safety of AZD9291 in Patients With Advanced Solid Tumours and Normal Liver Function or Mild or Moderate Liver Impairment

An Open-label, Non-randomised, Multicentre, Comparative, Phase I Study to Determine the Pharmacokinetics, Safety and Tolerability of AZD9291 Following a Single Oral Dose to Patients With Advanced Solid Tumours and Normal Hepatic Function or Mild or Moderate Hepatic Impairment

Rate and extent of absorption of AZD9291 following single oral doses of AZD9291 tablet formulation by assessment of maximum plasma AZD9291 concentration (Cmax).

Rate and extent of absorption of AZD9291 following single oral doses of AZD9291 tablet formulation by assessment of area under the plasma concentration time curve from zero to infinity (AUC).

Rate and extent of absorption of AZD9291 by assessment of AUC from time zero to last quantifiable dose AUC(0-t)

Assessment of the PK of AZ5104 and AZ7550 using maximum plasma concentration (Cmax).

Safety data collected using: Assessment of adverse events (AEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.0; Vital signs (blood pressure, pulse, temperature, height, weight); laboratory parameters (clinical chemistry, haematology, urinalysis); physical examination; and standard 12-lead electrocardiograms (ECGs)

Rate and extent of absorption of AZD9291, AZ5104, and AZ7550 by assessment of time to Cmax (tmax)

Rate and extent of absorption of AZD9291, AZ5104, and AZ7550 by assessment of AUC from time zero to t=24, AUC(0-24)

Rate and extent of absorption of AZD9291, AZ5104, and AZ7550 by assessment of AUC from time zero to t=72, AUC(0-72)

Rate and extent of absorption of AZD9291, AZ5104, and AZ7550 by assessment of AUC from time zero to t=168, AUC(0-168).

Rate and extent of absorption of AZD9291, AZ5104, and AZ7550 by assessment of terminal rate constant (λz).

Rate and extent of absorption of AZD9291, AZ5104, and AZ7550 by assessment of the terminal half-life (t1/2).

Rate and extent of absorption of AZD9291, AZ5104, and AZ7550 by assessment of renal clearance (CL(R).

Rate and extent of absorption of AZD9291 by assessment of the apparent clearance following oral administration (CL/F)

Rate and extent of absorption of AZD9291 by assessment of the apparent volume of distribution (Vz/F)

Assessment of the PK of AZ5104 and AZ7550 using area under the plasma concentration curve from zero extrapolated to infinity (AUC).

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Anti-Infective Agents

Rifampin

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Sequential treatments of AZD9291 alone followed by AZD9291 +rifampicin, followed by AZD9291 alone.

Rifampicin (CYP inducer) 600mg taken once daily from Day 29 to Day 49 (Part A)

Rifampicin

Part A: AZD9291 80mg tablet taken daily from Days 1 to 77. Part B: AZD9291 80mg tablet taken daily for 12 months.

Blood sampling to measure rifampicin levels

Pharmacokinetic sampling - rifampicin

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent.

Part A will assess the effect of rifampicin on the pharmacokinetic (PK) parameters of AZD9291 and metabolites AZ5104 and AZ7550 following multiple oral dosing of both rifampicin and AZD9291 in a fasted state.

Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients who complete Part A will be able to enter part B, and continue to receive AZD9291 80 mg once daily until: disease progression; they are no longer deriving clinical benefit; or any other reason.

Study to Assess the Effect of Rifampicin on Blood Levels and Safety of AZD9291, in Patients With EGFRm+ NSCLC

A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of Rifampicin (a CYP3A4 Inducer) on the Pharmacokinetics of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Rate and extent of absorption of AZD9291 by assessment of maximum plasma concentration at steady state (Css,max). AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).

Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).

Rate and extent of absorption of AZD9291 by assessment of Css,max. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).

Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).

Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).

Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2).

Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).

Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).

Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).

Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2).

Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of time to reach maximum plasma concentration at steady state (tss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).

Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2).

Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing alone and in combination with rifampicin (all periods).

Rate and extent of absorption of rifampicin by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing in combination with rifampicin (Period 2).

Rate and extent of absorption of AZD9291 by assessment of the apparent plasma clearance following oral administration and multiple dosing (CLss/F). AZD9291 dosing alone and in combination with rifampicin (all periods).

Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2).

Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for Css,max (MRCss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).

Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for AUCtau (MRAUCtau). AZD9291 dosing alone and in combination with rifampicin (all periods).

Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 77), or until 30 days after last dose if discontinued in Part A.

Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).

Overall

In Part A of the study, each patient received 80 mg oral doses of AZD9291 tablets once daily for 77 days (Days 1 to 77) and additionally received 600 mg oral doses of rifampicin once daily on Days 29 to 49.

Part A

In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation.

Part B

In Part A of the study, sequential treatments of AZD9291 alone, followed by AZD9291 + rifampicin, followed by AZD9291 alone. Each patient received 80 mg oral doses of AZD9291 tablets once daily for 77 days (Days 1 to 77) and additionally received 600 mg oral doses of rifampicin once daily on Days 29 to 49.

In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation.

AZD9291 and Rifampicin (Part A); AZD9291 Alone (Part B)

Race (NIH/OMB)

All patients in the safety analysis set who received at least one dose of AZD9291 (n = 41) were included in the baseline analysis.

At end of Part B, the CAP allowed patients to continue receiving AZD9291 if still deriving clinical benefit. No clinical data was databased during the CAP; thus AE data is presented to end of Part B only.

Natural log-transformed Css,max values were compared between periods using a mixed effects analysis of variance (ANOVA) with period as fixed effect and patient as random effect. It was assumed the within-patient coefficient of variation for AZD9291 in both area under the plasma concentration-time curve during the dosing interval (AUCtau) and Cmax was 34%. A 33% decrease in exposure for AZD9291 when given with rifampicin was also assumed.

AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.

AZD9291 Alone (Period 1)

Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.

AZD9291 + Rifampicin (Period 2)

The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.

Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max)

Natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as fixed effect and patient as random effect. It was assumed the within-patient coefficient of variation for AZD9291 in both AUCtau and Cmax was 34%. A 33% decrease in exposure for AZD9291 when given with rifampicin was also assumed.

Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau)

Natural log-transformed Css,max values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.

AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77.

AZD9291 Alone (Period 3)

Assessment of Css,Max for AZD9291 Before and After Rifampicin

For AZ5104 (metabolite), natural log-transformed Css,max values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.

Assessment of Css,Max for AZ5104 (Metabolite)

For AZ7550 (metabolite), natural log-transformed Css,max values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.

Assessment of Css,Max for AZ7550 (Metabolite)

Assessment of Css,Max for Rifampicin

Natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.

Assessment of AUCtau for AZD9291 Before and After Rifampicin

For AZ5104 (metabolite), natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.

Assessment of AUCtau for AZ5104 (Metabolite)

For AZ7550 (metabolite), natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Drug-Drug Interaction Study With AZD9291 and Omeprazole in Healthy Volunteers	NCT02224053	Healthy Volunte...	Pharmacokinetic... AZD9291 tablet ... Omeprazole tabl... Pharmacokinetic...	18 Years - 55 Years	AstraZeneca
Drug-Drug Interaction Study With AZD9291 and Omeprazole in Healthy Volunteers	NCT02224053	Healthy Volunte...	Pharmacokinetic... AZD9291 tablet ... Omeprazole tabl... Pharmacokinetic...	18 Years - 55 Years	AstraZeneca
Study to Assess the Blood Levels and Safety of AZD9291 in Patients With Advanced Solid Tumours and Normal Liver Function or Mild or Moderate Liver Impairment	NCT02161770	Solid Tumours	AZD9291 tablet ... Pharmacokinetic... Pharmacokinetic...	18 Years - 99 Years	AstraZeneca
Study to Assess the Effect of Rifampicin on Blood Levels and Safety of AZD9291, in Patients With EGFRm+ NSCLC	NCT02197247	Non Small Cell ...	Pharmacokinetic... Rifampicin AZD9291 tablet ... Pharmacokinetic... Pharmacokinetic...	18 Years - 130 Years	AstraZeneca

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