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

Blood samples taken pre and post dosing with AZD9291+/- itraconazole

Pharmacokinetic sampling

AZD9291 tablets: Part A 80mg od, days 1 and 10 only. Part B 80mg od for 12 months.

AZD9291

Itraconazole tablets: 2x100mg bd, Part A days 6 to 19 only

Serban Ghiorghiu, MSD

This is a 2 part study in patients with EGFRm+ non small cell lung cancer (NSCLC), whose disease has progressed on an EGFRm TKI, who are refractory or resistant to standard therapy. Part A will assess the effect of multiple oral doses of itraconazole on the single dose pharmacokinetic (PK) parameters of AZD9291. On completion of Part A, patients may continue to take AZD9291 tablets (Part B) following the collection of the 216 hour sample on Day 19 if they and the Investigator deem it appropriate, until such time as their disease progresses, the Investigator believes they are no longer deriving clinical benefit, or they stop taking AZD9291 for any other reason

Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of AZD9291, in Patients With EGFR Positive Non-small Cell Lung Cancer. Patients Will be Chosen From Those Who Have Already Been Prescribed an EGFR TKI Medicine (Such as Iressa or Tarceva)

A Phase I, Open-label, Non-randomised Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of a Single Oral Dose 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.

Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration

Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to infinity

Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 120 hours

Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration curve from time zero to last quantifiable dose

Pharmacokinetics of AZD9291 by assessment of time to Cmax

Pharmacokinetics of AZD9291 by assessment of the terminal half-life

Rate and extent of absorption of AZD9291 by assessment of apparent clearance following oral administration

Rate and extent of absorption of AZD9291 by assessment of the apprarent volume of distribution

Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of maximum plasma AZ5104 concentration

Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity

Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of maximum plasma AZ7550 concentration

Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity

AstraZeneca

Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 19), 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 a single 80 mg oral AZD9291 tablet dose in each of 2 treatment periods (AZD9291 dosing on Days 1 and 10). Patients additionally received itraconazole 200 mg twice daily dosing from Days 6 to 18.

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 (including a washout) followed by AZD9291+itraconazole. Each patient received single 80 mg oral doses of AZD9291 tablets on Days 1 and 10, and in addition received itraconazole capsules 200 mg twice daily on Days 6 to 18.

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 Itraconozole (Part A); AZD9291 Alone (Part B)

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

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.

Dr Karen So

Study sized so experiment-wise power for the upper bound of the 90% CIs of geometric mean ratios for both AUC and Cmax of AZD9291 being below 200% was 90% (95% for each parameter). Within patient CV assumed to be 34%. A 50% increase in exposure was also assumed.

Single oral dose of 80mg AZD9291 on Day 1

AZD9291 Alone

Single oral dose 80mg AZD9291 on Day 10, itraconazole 200mg twice daily dosing on Days 6-18

AZD9291+Itraconazole

All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine outcome measure without important protocol deviations/violations and excluding Period 2 data for patients meeting carry-over exclusion criterion (defined as Period 2 pre-dose concentration \>10% of Cmax).

Cmax of AZD9291

AUC of AZD9291

AUC(0-120) of AZD9291

AUC(0-t) of AZD9291

Tmax of AZD9291

t1/2 of AZD9291

CL/F of AZD9291

Vz/F of AZD9291

All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine outcome measure without important protocol deviations/violations and excluding Period 2 data for patients meeting carry-over exclusion criterion (defined as Period 2 pre-dose AZ5104 concentration \>20% of Cmax).

Cmax of AZ5104

AUC of AZ5104

All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine outcome measure without important protocol deviations/violations and including Period 2 data (since all patients met carry over criteria of Period 2 pre-dose AZ7550 concentration \>20% of Cmax).

Cmax of AZ7550

All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine outcome measure without important protocol deviations, where AUC possible to calculate, and including Period 2 data (all patients met carry over criteria of Period 2 pre-dose AZ7550 concentration \>20% of Cmax).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of AZD9291, in Patients With EGFR Positive Non-small Cell Lung Cancer. Patients Will be Chosen From Those Who Have Already Been Prescribed an EGFR TKI Medicine (Such as Iressa or Tarceva)	NCT02157883	Advanced Non Sm... Advanced (Inope...	Pharmacokinetic... AZD9291 Itraconazole	18 Years - 99 Years	AstraZeneca
Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of AZD9291, in Patients With EGFR Positive Non-small Cell Lung Cancer. Patients Will be Chosen From Those Who Have Already Been Prescribed an EGFR TKI Medicine (Such as Iressa or Tarceva)	NCT02157883	Advanced Non Sm... Advanced (Inope...	Pharmacokinetic... AZD9291 Itraconazole	18 Years - 99 Years	AstraZeneca

Spots Global Cancer Trial Database for advanced (inoperable) non small cell lung cancer