Study to Assess the Effect of AZD9291 on the Blood Levels... | NCT02317016

Label	Type	Description	Intervention Names
AZD9291 and rosuvastatin	Experimental	Sequential treatments of rosuvastatin alone followed by AZD9291 alone, followed by rosuvastatin + AZD9291.	Procedure: Pharmacokinetic sampling - AZD9291 Drug: AZD9291 tablet dosing Drug: Rosuvastatin Procedure: Pharmacokinetic sampling - rosuvastatin Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550

Name	Type	Description	Arm Group Labels	Other Names
Pharmacokinetic sampling - AZD9291	Procedure	Blood sampling to measure AZD9291	AZD9291 and rosuvastatin

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Assessment of Maximum Plasma Concentration (Cmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291	Rate and extent of absorption of rosuvastatin by assessment of Cmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1 [Period 1] and Day 32 [Period 3], respectively).	Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.
Assessment of AUC From Time Zero Extrapolated to Infinity for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291	Rate and extent of absorption of rosuvastatin by assessment of AUC from time zero extrapolated to infinity. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).	Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Secondary Outcomes

Measure	Description	Time Frame
Assessment of Time to Maximum Plasma Concentration (Tmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291	Rate and extent of absorption of rosuvastatin by assessment of tmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).	Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Eligibility Module

Eligibility Criteria

For inclusion in the study patients must fulfil the following criteria:

Male or female, aged at least 18 years.
Histological or cytological confirmation diagnosis of NSCLC.
Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI, eg, gefitinib, erlotinib or afatinib. In addition, other lines of therapy may have been given. All patients must have documented radiological progression on the last treatment administered prior to enrolling in the study.
Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).
Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks (Appendix G).
Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening.
Females should be using adequate contraceptive measures and must have a negative pregnancy test prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments; Women under 50 years old would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinising hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range for the institution; Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not tubal ligation.
Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
Male patients should be willing to use barrier contraception, ie, condoms.

Exlusion Criteria:

Participation in another clinical study with an IP in last 14 days (or longer depending on the defined characteristics of the agents used).
Any patient of Asian ethnicity or has a parent who is of Asian ethnicity (eg, Chinese, Filipino, Japanese, Korean and Vietnamese). If only a grandparent is Asian, this is acceptable. Asian Indians are acceptable.
Treatment w/ any of the following: an EGFR TKI (eg, erlotinib, gefitinib or afatinib) within 8 days or approx. 5 x half-life, whichever is the longer, of the first dose of study treatment; Any cytotoxic chemotherapy, investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment; Major surgery (excluding placement of vascular access) w/in 4 weeks of the 1st dose of study treatment; Radiotherapy with a limited field of radiation for palliation w/in 1 week of the first dose of study treatment, with the exception of patients receiving radiation to more than 30% of bone marrow or with a wide field of radiation which must be completed w/in 4 weeks of the 1st dose of study treatment; Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inhibitors of CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior). All patients must avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer/inhibitory effects on CYP3A4.
Unresolved toxicities from prior therapy > CTCAE Grade 1 at the study start besides alopecia and Grade 2, prior platinum-therapy related neuropathy.
Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first administration of the IP until the final PK sample collection on Day 35 of Part A.
Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the PI's opinion makes it undesirable for the patient to participate in the study or which would jeopardise compliance with the protocol, or active infection including hep B, hep C and HIV. Screening for chronic conditions is not required.
Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: ANC<1.5 x 10^9/L; Platelet count <100 x 10^9/L; Haemoglobin <90 g/L; ALT >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases; AST >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases; Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases; Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN.
Any of the following cardiac criteria: Mean resting corrected QT interval corrected for heart rate using Fridericia's correction factor (QTcF) >470 msec obtained from 3 ECGs; Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250 msec; Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
Patients unable to swallow orally administered medication or patients with gastrointestinal disorders or significant gastrointestinal resection likely to interfere with the absorption of AZD9291.
Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
Women who are breastfeeding.
Patients with a known hypersensitivity to AZD9291 or rosuvastatin or any of the excipients of the products.
Concomitant medication contraindicated for use with rosuvastatin due to drug interaction and/or associated with increased risk of rhabdomyolysis (including, but not limited to): fibrates (eg, gemfibrozil, fenofibrate), niacin, cyclosporine, lopinavir/ritonavir or atazanavir/ritonavir and colchinine.
Past medical history of drug-related rhabdomyolysis and/or myalgia.
Use of 3-hydroxy-3-methyl-glutaryl coenzyme A-reductase inhibitors, such as lovastatin and simvastatin (Part A only).

Name	Affiliation	Role
Serban Ghiorghiu, MSD	AstraZeneca	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Fairfax	Virginia	22031	United States
Research Site

PubMed Identifier	Type	Citation	Retractions
30171779	Derived	Harvey RD, Aransay NR, Isambert N, Lee JS, Arkenau T, Vansteenkiste J, Dickinson PA, Bui K, Weilert D, So K, Thomas K, Vishwanathan K. Effect of multiple-dose osimertinib on the pharmacokinetics of simvastatin and rosuvastatin. Br J Clin Pharmacol. 2018 Dec;84(12):2877-2888. doi: 10.1111/bcp.13753. Epub 2018 Oct 10.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Rosuvastatin and AZD9291 (Part A); AZD9291 Alone (Part B)	In Part A of the study, sequential treatments of rosuvastatin alone, followed by AZD9291 alone, followed by rosuvastatin + AZD9291. Each patient received 20 mg single oral doses of rosuvastatin on Day 1 and Day 32, and 80 mg oral doses of AZD9291 tablets once daily for 31 days (Days 4 to 34). In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

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

Assessment of Maximum Plasma Concentration (Cmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Rate and extent of absorption of rosuvastatin by assessment of Cmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1 [Period 1] and Day 32 [Period 3], respectively).

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

nanogram per millilitre (ng/mL)

Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

ID	Title	Description
OG000	Rosuvastatin Alone (Period 1 [Day 1])	Rosuvastatin 20 mg single oral dose on Day 1 (Part A). Rosuvastatin 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 dose.
OG001	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Units	Counts
Participants	OG00042 OG00139

Title

Denominators

Categories

Title	Measurements
	OG00013.96± 66.7 OG00124.03± 70.5

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Natural log-transformed Cmax values were compared between treatments using a mixed effects analysis of variance (ANOVA) with treatment as a fixed effect and patient as a random effect. It was assumed the within-patient coefficient of variation for rosuvastatin in both area under the plasma concentration-time curve (AUC) and Cmax was 41%. No change in the exposure for rosuvastatin when given with AZD9291 was also assumed.					Geometric least-squares (LS) mean ratio	171.92			2-Sided	90	145.94	202.53			AZD9291+ rosuvastatin / rosuvastatin alone (Day 32 versus Day 1).		Non-Inferiority or Equivalence

Primary

Assessment of AUC From Time Zero Extrapolated to Infinity for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Rate and extent of absorption of rosuvastatin by assessment of AUC from time zero extrapolated to infinity. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng * h o u r per mL (ng*h/mL )

Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

ID	Title	Description
OG000	Rosuvastatin Alone (Period 1 [Day 1])	Rosuvastatin 20 mg single oral dose on Day 1 (Part A). Rosuvastatin 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 dose.
OG001	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Secondary

Assessment of Time to Maximum Plasma Concentration (Tmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Rate and extent of absorption of rosuvastatin by assessment of tmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

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.

Posted

Median

Full Range

Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

ID	Title	Description
OG000	Rosuvastatin Alone (Period 1 [Day 1])	Rosuvastatin 20 mg single oral dose on Day 1 (Part A). Rosuvastatin 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 dose.
OG001	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Secondary

Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration at Time "t" (AUC0-t) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Rate and extent of absorption of rosuvastatin by assessment of AUC0-t. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*h/mL

Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

ID	Title	Description
OG000	Rosuvastatin Alone (Period 1 [Day 1])	Rosuvastatin 20 mg single oral dose on Day 1 (Part A). Rosuvastatin 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 dose.
OG001	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Secondary

Assessment of Apparent Plasma Clearance (CL/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Rate and extent of absorption of rosuvastatin by assessment of CL/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

Litre / h (L/h)

Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

ID	Title	Description
OG000	Rosuvastatin Alone (Period 1 [Day 1])	Rosuvastatin 20 mg single oral dose on Day 1 (Part A). Rosuvastatin 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 dose.
OG001	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Secondary

Assessment of Apparent Volume of Distribution (Vz/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Rate and extent of absorption of rosuvastatin by assessment of Vz/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

ID	Title	Description
OG000	Rosuvastatin Alone (Period 1 [Day 1])	Rosuvastatin 20 mg single oral dose on Day 1 (Part A). Rosuvastatin 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 dose.
OG001	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Secondary

Assessment of Terminal Elimination Half-life (t1/2[lambda_z]) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Rate and extent of absorption of rosuvastatin by assessment of t1/2(lambda_z). Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

ID	Title	Description
OG000	Rosuvastatin Alone (Period 1 [Day 1])	Rosuvastatin 20 mg single oral dose on Day 1 (Part A). Rosuvastatin 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 dose.
OG001	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Secondary

Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval (AUCtau) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of AUCtau. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

nanomolar * h (nM*h)

Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

ID	Title	Description
OG000	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Secondary

Assessment of Maximum Plasma Concentration at Steady State (Css,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

ID	Title	Description
OG000	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Secondary

Assessment of Time to Reach Maximum Plasma Concentration at Steady State (Tss,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of tss,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

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.

Posted

Median

Full Range

Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

ID	Title	Description
OG000	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Secondary

Assessment of Minimum Plasma Concentration at Steady State (Css,Min) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,min over the dosing interval. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

ID	Title	Description
OG000	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Secondary

Assessment of Apparent Plasma Clearance at Steady State (CLss/F) for AZD9291 Following Administration of AZD9291 and Rosuvastatin Together

Rate and extent of absorption for AZD9291 by assessment of CLss/F after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

L/h

Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

ID	Title	Description
OG000	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Units	Counts

Secondary

Assessment of the Metabolite to Parent Ratios of Css,Max (MRCss,Max) for AZ5104 and AZ7550 Following Administration of AZD9291 and Rosuvastatin Together

Assessment of MRCss,max for AZ5104 and AZ7550 (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

Ratio

Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

ID	Title	Description
OG000	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Secondary

Assessment of the Metabolite to Parent Ratios of AUCtau (MRAUCtau) for AZ5104 and AZ7550 Following Administration of AZD9291 and Rosuvastatin Together

Assessment of MRAUCtau for AZ5104 and AZ7550 (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

Ratio

Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

ID	Title	Description
OG000	AZD9291 + Rosuvastatin (Period 3 [Day 32])	Steady state AZD9291 80 mg in combination with rosuvastatin 20 mg single oral dose on Day 32 (Part A). The Day 32 treatment (AZD9291 plus rosuvastatin) could occur within a window of ±2 days. Treatment 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 dose. Previously, patients had received AZD9291 80 mg once daily for 28 days during Period 2 (Days 4 to 31), and after Day 32 in Period 3 (Days 33 and 34) patients also received AZD9291 80 mg once daily doses.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected44 at risk EG0021 events1 affected42 at risk
Fatigue	General disorders	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected44 at risk EG0021 events1 affected42 at risk
Pneumonia	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected44 at risk EG0021 events1 affected42 at risk
Pneumonia pseudomonal	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected44 at risk EG0021 events1 affected42 at risk
Blood creatine phosphokinase increased	Investigations	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0011 events1 affected44 at risk EG0020 events0 affected42 at risk
Transaminases increased	Investigations	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected44 at risk EG0021 events1 affected42 at risk
Transient ischaemic attack	Nervous system disorders	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected44 at risk EG0021 events1 affected42 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA 19.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected44 at risk EG0021 events1 affected42 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA 19.0	Systematic Assessment	EG0002 events1 affected44 at risk EG0011 events1 affected44 at risk EG0021 events1 affected42 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 19.0	Systematic Assessment	EG0006 events4 affected44 at risk EG0013 events3 affected44 at risk EG0023 events2 affected42 at risk
Constipation	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0007 events6 affected44 at risk EG0014 events4 affected44 at risk EG0023 events3 affected42 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG00027 events13 affected44 at risk EG00112 events9 affected44 at risk EG00215 events9 affected42 at risk
Vomiting	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0005 events3 affected44 at risk EG0012 events2 affected44 at risk EG0023 events2 affected42 at risk
Fatigue	General disorders	MedDRA 19.0	Systematic Assessment	EG0009 events8 affected44 at risk EG0015 events5 affected44 at risk EG0024 events3 affected42 at risk
Blood creatine phosphokinase increased	Investigations	MedDRA 19.0	Systematic Assessment	EG0003 events3 affected44 at risk EG0010 events0 affected44 at risk EG0023 events3 affected42 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 19.0	Systematic Assessment	EG0009 events6 affected44 at risk EG0012 events2 affected44 at risk EG0027 events5 affected42 at risk
Vertigo	Ear and labyrinth disorders	MedDRA 19.0	Systematic Assessment	EG0005 events3 affected44 at risk EG0012 events2 affected44 at risk EG0023 events3 affected42 at risk
Dry eye	Eye disorders	MedDRA 19.0	Systematic Assessment	EG0003 events3 affected44 at risk EG0010 events0 affected44 at risk EG0023 events3 affected42 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0004 events3 affected44 at risk EG0012 events2 affected44 at risk EG0022 events2 affected42 at risk
Nausea	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0008 events7 affected44 at risk EG0014 events4 affected44 at risk EG0024 events3 affected42 at risk
Stomatitis	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0004 events3 affected44 at risk EG0011 events1 affected44 at risk EG0023 events3 affected42 at risk
Asthenia	General disorders	MedDRA 19.0	Systematic Assessment	EG00012 events9 affected44 at risk EG0014 events4 affected44 at risk EG0028 events7 affected42 at risk
Pyrexia	General disorders	MedDRA 19.0	Systematic Assessment	EG0007 events6 affected44 at risk EG0013 events3 affected44 at risk EG0024 events4 affected42 at risk
Xerosis	General disorders	MedDRA 19.0	Systematic Assessment	EG0003 events3 affected44 at risk EG0011 events1 affected44 at risk EG0022 events2 affected42 at risk
Paronychia	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG00011 events6 affected44 at risk EG0011 events1 affected44 at risk EG00210 events5 affected42 at risk
Rhinitis	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0004 events4 affected44 at risk EG0012 events2 affected44 at risk EG0022 events2 affected42 at risk
Urinary tract infection	Infections and infestations	MedDRA 19.0	Systematic Assessment	EG0004 events4 affected44 at risk EG0013 events3 affected44 at risk EG0021 events1 affected42 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA 19.0	Systematic Assessment	EG00019 events16 affected44 at risk EG0019 events9 affected44 at risk EG00210 events9 affected42 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 19.0	Systematic Assessment	EG0006 events6 affected44 at risk EG0014 events4 affected44 at risk EG0022 events2 affected42 at risk
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA 19.0	Systematic Assessment	EG0005 events5 affected44 at risk EG0010 events0 affected44 at risk EG0025 events5 affected42 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA 19.0	Systematic Assessment	EG0005 events5 affected44 at risk EG0014 events4 affected44 at risk EG0021 events1 affected42 at risk
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA 19.0	Systematic Assessment	EG0005 events5 affected44 at risk EG0014 events4 affected44 at risk EG0021 events1 affected42 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 19.0	Systematic Assessment	EG0005 events5 affected44 at risk EG0013 events3 affected44 at risk EG0022 events2 affected42 at risk
Headache	Nervous system disorders	MedDRA 19.0	Systematic Assessment	EG0008 events6 affected44 at risk EG0012 events2 affected44 at risk EG0026 events4 affected42 at risk
Insomnia	Psychiatric disorders	MedDRA 19.0	Systematic Assessment	EG0005 events4 affected44 at risk EG0012 events2 affected44 at risk EG0023 events2 affected42 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 19.0	Systematic Assessment	EG00015 events11 affected44 at risk EG0014 events4 affected44 at risk EG00211 events8 affected42 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 19.0	Systematic Assessment	EG00012 events12 affected44 at risk EG0018 events8 affected44 at risk EG0024 events4 affected42 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 19.0	Systematic Assessment	EG0004 events3 affected44 at risk EG0011 events1 affected44 at risk EG0023 events2 affected42 at risk
Dermatitis acneiform	Skin and subcutaneous tissue disorders	MedDRA 19.0	Systematic Assessment	EG0006 events5 affected44 at risk EG0012 events2 affected44 at risk EG0024 events4 affected42 at risk
Dry skin	Skin and subcutaneous tissue disorders	MedDRA 19.0	Systematic Assessment	EG0008 events6 affected44 at risk EG0011 events1 affected44 at risk EG0027 events5 affected42 at risk
Palmar-plantar erythrodysaesthesia syndrome	Skin and subcutaneous tissue disorders	MedDRA 19.0	Systematic Assessment	EG0003 events3 affected44 at risk EG0012 events2 affected44 at risk EG0021 events1 affected42 at risk

ID	Term
D002289	Carcinoma, Non-Small-Cell Lung
D009369	Neoplasms

ID	Term
D002283	Carcinoma, Bronchogenic
D001984	Bronchial Neoplasms
D008175	Lung Neoplasms
D012142	Respiratory Tract Neoplasms
D013899	Thoracic Neoplasms
D009371	Neoplasms by Site
D008171	Lung Diseases
D012140	Respiratory Tract Diseases

ID	Term
D013449	Sulfonamides
D000577	Amides
D009930	Organic Chemicals
D005464	Fluorobenzenes
D006845	Hydrocarbons, Fluorinated
D006846	Hydrocarbons, Halogenated
D006838	Hydrocarbons
D013450	Sulfones
D013457	Sulfur Compounds
D011743	Pyrimidines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Overall Safety Population	Parts A and B of the study combined.	7	44	40	44
EG001	Part A Safety Population	In Part A of the study, each patient received 80 mg oral doses of AZD9291 tablets once daily for 31 days (Days 4 to 34) and single 20 mg oral doses of rosuvastatin on Day 1 and Day 32.	2	44	34	44
EG002	Part B Safety Population	In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation.	6	42	29	42