Advanced Non Small Cell Lung Cancer, Advanced (Inoperable) Non Small Cell Lung Cancer
Conditions
Keywords
oncology, cancer, non small cell lung cancer, anticancer drug, pharmacokinetics, AZD9291, EGFR sensitivity mutation, food effect
Brief summary
This is a 2-part study in patients with epidermal growth factor receptor mutation positive (EGFRm+) non-small cell lung cancer (NSCLC) whose disease has progressed on treatment with an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI): Part A will determine the effect of food on the pharmacokinetics (PK) of AZD9291; Part B will allow patients further access to AZD9291 and will provide for additional safety data collection. Part A is a randomised, open-label, 2 treatment period crossover study in which patients will each receive a single oral dose of AZD9291 (1 x 80 mg tablet) at breakfast time (approximately 0800) in each of 2 treatment periods (once immediately following a high fat meal \[fed\], and once in the fasted state \[fasted\]), with a washout period of 9 days between doses. Approximately 38 patients are planned to be enrolled and dosed; at least 30 evaluable patients will be required to complete Part A (ie, the last PK sample in Treatment Period 2 \[TP 2\] has been collected). Additional patients may be enrolled to allow for at least 30 evaluable patients
Interventions
DRUGAZD9291 tablets
AZD9291 tablets: Part A 80mg od, days 1 and 10 only. Part B 80mg od for 12 months.
PROCEDUREPharmacokinetic sampling - AZD9291
Blood samples taken pre and post dosing of AZD9291 following either a period of fasting or consumption of a meal.
OTHERDietary Fasted
Fasted from 10 hours prior to dosing with 80mg AZD9291 tablet and 4 hours after dosing
OTHERDietary High Fat
Allocated breakfast prior to dosing with 80mg AZD9291 tablet
Blood samples taken pre and post dosing of AZD9291 following either a period of fasting or consumption of a meal.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria: 1. Male or female, aged at least 18 years. 2. Able to eat a high-fat meal within a 30-minute period, as provided by the study site. 3. Histologically or, where appropriate, cytologically confirmed NSCLC. 4. Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI. 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. 5. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 6. ECOG performance status 0-1 with no deterioration over the previous 2 weeks. 7. Patients must have a life expectancy of ≥12 weeks, as estimated at the time of screening. 8. 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 luteinizing hormone and follicle stimulating hormone 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. 9. Male patients should be willing to use barrier contraception, ie, condoms, until 6 months after last study drug is taken. Patients should not enter the study if any of the following
Exclusion criteria
are fulfilled: 1. Participation in another clinical study with an IP during the last 14 days (or a longer period depending on the defined characteristics of the agents used). 2. Treatment with any of the following: Treatment with an EGFR TKI w/in 8 days or approximately 5x half-life, whichever is the longer, of the first dose of study treatment; Any cytotoxic chemotherapy, investigational agents or other anticancer drugs w/in 14 days of the first dose of study treatment; Major surgery (excluding placement of vascular access) within 4 weeks of the first dose; Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment, with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation which must be completed within 4 weeks of the first 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 CYP2C8 and of CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer/inhibitory effects on CYP3A4, CYP2C8, and/ or CYP1A2. 3. 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 end of Part A. 4. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum therapy related neuropathy. 5. Patients unable to fast for up to 14 hours. 6. Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment. 7. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator'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 hepatitis B, hepatitis C and human immunodeficiency virus. Screening for chronic conditions is not required. 8. Patients with type I diabetes. 9. Patients unable to swallow orally administered medication or patients with gastrointestinal disorders or significant gastrointestinal resection likely to interfere with the absorption of AZD9291. 10. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. 11. Women who are breastfeeding. 12. Patients with a known hypersensitivity to AZD9291 13. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: Absolute neutrophil count (ANC) \<1.5 x 109/L; Platelet count \<100 x 109/L; Haemoglobin \<90 g/L; ALT \>2.5 x the institutional ULN if no demonstrable liver metastases or \>5 x institutional ULN in the presence of liver metastases; AST \>2.5 x institutional ULN if no demonstrable liver metastases or \>5 x institutional ULN in the presence of liver metastases; Total bilirubin \>1.5 x institutional ULN if no liver metastases or \>3 x institutional ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases; Creatinine \>1.5 x institutional ULN concurrent with creatinine clearance \<50 mL/min (measured or calculated by Cockcroft-Gault formula); confirmation of creatinine clearance is only required when creatinine is \>1.5 x institutional ULN. 14. 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. 15. For optional genetic research: Previous allogenic bone marrow transplant or non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC(0-72) of AZD9291 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post AZD9291 dose in Part A. | Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 72 hours. |
| Cmax of AZD9291 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A. | Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC(0-120) of AZD9291 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post AZD9291 dose in Part A. | Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 120 hours. |
| Tmax of AZD9291 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A. | Pharmacokinetics of AZD9291 by assessment of time to Cmax. |
| t1/2 of AZD9291 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A. | Pharmacokinetics of AZD9291 by assessment of the terminal half-life. |
| CL/F of AZD9291 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A. | Rate and extent of absorption of AZD9291 by assessment of apparent clearance following oral administration. |
| Vz/F of AZD9291 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A. | Rate and extent of absorption of AZD9291 by assessment of the apprarent volume of distribution. |
| AUC of AZD9291 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A. | Area under the plasma concentration curve from zero extrapolated to infinity. |
| Cmax of AZ5104 and AZ7550 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A. | Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of maximum plasma concentration. |
| AUC(0-t) of AZ5104 and AZ7550 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A. | Area under the plasma concentration curve from time zero to last quantifiable dose for AZ5104 and AZ7550 (metabolites to AZD9291). |
| AUC(0-120) of AZ5104 and AZ7550 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post AZD9291 dose in Part A. | Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of area under the plasma concentration time curve from zero to 120 hours. |
| Tmax of AZ5104 and AZ7550 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A. | Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of time to Cmax. |
| t1/2 of AZ5104 and AZ7550 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A. | Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of the terminal half-life. |
| AUC(0-72) of AZ5104 and AZ7550 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post AZD9291 dose in Part A. | Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of area under the plasma concentration time curve from zero to 72 hours. |
| AUC(0-t) of AZD9291 | Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A. | Area under the plasma concentration curve from time zero to last quantifiable dose. |
Countries
France, South Korea, Spain, United Kingdom
Participant flow
Recruitment details
First subject enrolled: 14 November 2014; Last Subject Last Visit for Part A: 23 March 2015 and Part B: 22 March 2016. The study was performed at 12 sites across Asia and Western Europe. Part A determined effect of food on PK of AZD9291; Part B allowed subjects further access to AZD9291 and provided additional safety data.
Pre-assignment details
43 subjects were enrolled (signed informed consent). Subjects were assigned to treatment if they met all the inclusion and none of the exclusion criteria. 5 subjects were enrolled but failed inclusion/exclusion criteria and so were not eligible to be assigned treatment. The remaining 38 subjects started Period 1 and received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Fed/Fasted In Part A of the study, each patient received a single 80 mg oral AZD9291 tablet dose in each of 2 treatment periods. Patients who were randomised to the Fed/Fasted treatment group followed Sequence 1: AZD9291 tablets following a high-fat meal in Period 1, then AZD9291 tablets following a period of fasting in Period 2. | 18 |
| Fasted/Fed In Part A of the study, each patient received a single 80 mg oral AZD9291 tablet dose in each of 2 treatment periods. Patients who were randomised to the Fasted/Fed treatment group followed Sequence 2: AZD9291 tablets following a period of fasting in Period 1, then AZD9291 tablets following a high-fat meal in Period 2. | 20 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part B: Day 15 to End Part B (AZD9291) | Death | 0 | 0 | 5 |
| Part B: Day 15 to End Part B (AZD9291) | Disease progression | 0 | 0 | 19 |
Baseline characteristics
| Characteristic | Fasted/Fed | Total | Fed/Fasted |
|---|---|---|---|
| Age, Continuous | 61.4 Years STANDARD_DEVIATION 11 | 62.7 Years STANDARD_DEVIATION 11.4 | 64.1 Years STANDARD_DEVIATION 11.98 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 31 Participants | 14 Participants |
| Sex: Female, Male Female | 10 Participants | 26 Participants | 16 Participants |
| Sex: Female, Male Male | 10 Participants | 12 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 38 | 0 / 38 | 2 / 38 |
| other Total, other adverse events | 38 / 38 | 20 / 38 | 37 / 38 |
| serious Total, serious adverse events | 8 / 38 | 1 / 38 | 7 / 38 |
Outcome results
Primary
AUC(0-72) of AZD9291
Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 72 hours.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter without important protocol deviations/violations and excluding Period 2 data for patients meeting carry-over exclusion criterion (defined as Period 2 pre-dose concentration \>5% of Cmax).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Fed (High-fat Meal) | AUC(0-72) of AZD9291 | 7403 nM*h |
| Fasted | AUC(0-72) of AZD9291 | 7345 nM*h |
Comparison: Study sized so experiment-wise power for the 90% CIs of geometric mean ratios for both AUC and Cmax of AZD9291 being within 70-143% was 90% (95% for each parameter). Within patient CV assumed to be 34%. A 6% change in exposure was also assumed.90% CI: [94.82, 118.6]
Primary
Cmax of AZD9291
Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.
Population: All patients had at least 1 dose AZD9291 and had sufficient postdose PK to determine parameter without important protocol deviations and excluding Period 2 data for patients meeting carry-over exclusion criterion (defined as Period 2 pre-dose concentration \>5% of Cmax). Note 1 patient missing key 8 hour sample so not included in Cmax analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Fed (High-fat Meal) | Cmax of AZD9291 | 199.6 nM |
| Fasted | Cmax of AZD9291 | 218.0 nM |
Comparison: Study sized so experiment-wise power for the 90% CIs of geometric mean ratios for both AUC and Cmax of AZD9291 being within 70-143% was 90% (95% for each parameter). Within patient CV assumed to be 34%. A 6% change in exposure was also assumed.90% CI: [81.4, 105.68]
Secondary
AUC(0-120) of AZ5104 and AZ7550
Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of area under the plasma concentration time curve from zero to 120 hours.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter 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 for respective metabolite).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Fed (High-fat Meal) | AUC(0-120) of AZ5104 and AZ7550 | AZ5104 | 744.4 nM*h |
| Fed (High-fat Meal) | AUC(0-120) of AZ5104 and AZ7550 | AZ7550 | 373.4 nM*h |
| Fasted | AUC(0-120) of AZ5104 and AZ7550 | AZ5104 | 875.7 nM*h |
| Fasted | AUC(0-120) of AZ5104 and AZ7550 | AZ7550 | 411.4 nM*h |
Secondary
AUC(0-120) of AZD9291
Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 120 hours.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter without important protocol deviations/violations and excluding Period 2 data for patients meeting carry-over exclusion criterion (defined as Period 2 pre-dose concentration \>5% of Cmax).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Fed (High-fat Meal) | AUC(0-120) of AZD9291 | 9549 nM*h |
| Fasted | AUC(0-120) of AZD9291 | 9308 nM*h |
Secondary
AUC(0-72) of AZ5104 and AZ7550
Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of area under the plasma concentration time curve from zero to 72 hours.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter 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 for respective metabolite).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Fed (High-fat Meal) | AUC(0-72) of AZ5104 and AZ7550 | AZ7550 | 235.0 nM*h |
| Fed (High-fat Meal) | AUC(0-72) of AZ5104 and AZ7550 | AZ5104 | 497.6 nM*h |
| Fasted | AUC(0-72) of AZ5104 and AZ7550 | AZ7550 | 266.4 nM*h |
| Fasted | AUC(0-72) of AZ5104 and AZ7550 | AZ5104 | 613.2 nM*h |
Comparison: AZ510490% CI: [57.86, 113.83]
Comparison: AZ755090% CI: [65.21, 119.32]
Secondary
AUC(0-t) of AZ5104 and AZ7550
Area under the plasma concentration curve from time zero to last quantifiable dose for AZ5104 and AZ7550 (metabolites to AZD9291).
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter 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 for respective metabolite).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Fed (High-fat Meal) | AUC(0-t) of AZ5104 and AZ7550 | AZ5104 | 1033 nM*h |
| Fed (High-fat Meal) | AUC(0-t) of AZ5104 and AZ7550 | AZ7550 | 584.5 nM*h |
| Fasted | AUC(0-t) of AZ5104 and AZ7550 | AZ5104 | 1132 nM*h |
| Fasted | AUC(0-t) of AZ5104 and AZ7550 | AZ7550 | 591.9 nM*h |
Secondary
AUC(0-t) of AZD9291
Area under the plasma concentration curve from time zero to last quantifiable dose.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter without important protocol deviations/violations and excluding Period 2 data for patients meeting carry-over exclusion criterion (defined as Period 2 pre-dose concentration \>5% of Cmax).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Fed (High-fat Meal) | AUC(0-t) of AZD9291 | 10820 nM*h |
| Fasted | AUC(0-t) of AZD9291 | 10630 nM*h |
Secondary
AUC of AZD9291
Area under the plasma concentration curve from zero extrapolated to infinity.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter without important protocol deviations/violations and excluding Period 2 data for patients meeting carry-over exclusion criterion (defined as Period 2 pre-dose concentration \>5% of Cmax).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Fed (High-fat Meal) | AUC of AZD9291 | 11640 nM*h |
| Fasted | AUC of AZD9291 | 12530 nM*h |
Secondary
CL/F of AZD9291
Rate and extent of absorption of AZD9291 by assessment of apparent clearance following oral administration.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter without important protocol deviations/violations and excluding Period 2 data for patients meeting carry-over exclusion criterion (defined as Period 2 pre-dose concentration \>5% of Cmax).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Fed (High-fat Meal) | CL/F of AZD9291 | 13.75 L/h |
| Fasted | CL/F of AZD9291 | 12.78 L/h |
Secondary
Cmax of AZ5104 and AZ7550
Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of maximum plasma concentration.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter 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 for respective metabolite).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Fed (High-fat Meal) | Cmax of AZ5104 and AZ7550 | AZ5104 | 9.163 nM |
| Fed (High-fat Meal) | Cmax of AZ5104 and AZ7550 | AZ7550 | 4.236 nM |
| Fasted | Cmax of AZ5104 and AZ7550 | AZ5104 | 11.95 nM |
| Fasted | Cmax of AZ5104 and AZ7550 | AZ7550 | 5.109 nM |
Comparison: AZ510490% CI: [55.31, 106.32]
Comparison: AZ755090% CI: [60.99, 112.74]
Secondary
t1/2 of AZ5104 and AZ7550
Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of the terminal half-life.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter 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 for respective metabolite).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Fed (High-fat Meal) | t1/2 of AZ5104 and AZ7550 | AZ5104 | 64.74 h |
| Fed (High-fat Meal) | t1/2 of AZ5104 and AZ7550 | AZ7550 | 85.26 h |
| Fasted | t1/2 of AZ5104 and AZ7550 | AZ5104 | 62.89 h |
| Fasted | t1/2 of AZ5104 and AZ7550 | AZ7550 | 91.54 h |
Secondary
t1/2 of AZD9291
Pharmacokinetics of AZD9291 by assessment of the terminal half-life.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter without important protocol deviations/violations and excluding Period 2 data for patients meeting carry-over exclusion criterion (defined as Period 2 pre-dose concentration \>5% of Cmax).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Fed (High-fat Meal) | t1/2 of AZD9291 | 52.82 h |
| Fasted | t1/2 of AZD9291 | 54.64 h |
Secondary
Tmax of AZ5104 and AZ7550
Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of time to Cmax.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter 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 for respective metabolite).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Fed (High-fat Meal) | Tmax of AZ5104 and AZ7550 | AZ5104 | 24.17 h |
| Fed (High-fat Meal) | Tmax of AZ5104 and AZ7550 | AZ7550 | 24.60 h |
| Fasted | Tmax of AZ5104 and AZ7550 | AZ5104 | 8.03 h |
| Fasted | Tmax of AZ5104 and AZ7550 | AZ7550 | 10.00 h |
Secondary
Tmax of AZD9291
Pharmacokinetics of AZD9291 by assessment of time to Cmax.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter without important protocol deviations/violations and excluding Period 2 data for patients meeting carry-over exclusion criterion (defined as Period 2 pre-dose concentration \>5% of Cmax).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fed (High-fat Meal) | Tmax of AZD9291 | 7.97 h |
| Fasted | Tmax of AZD9291 | 6.08 h |
Secondary
Vz/F of AZD9291
Rate and extent of absorption of AZD9291 by assessment of the apprarent volume of distribution.
Time frame: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.
Population: All patients who received at least 1 dose of AZD9291 and had sufficient postdose PK assessments to determine parameter without important protocol deviations/violations and excluding Period 2 data for patients meeting carry-over exclusion criterion (defined as Period 2 pre-dose concentration \>5% of Cmax).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Fed (High-fat Meal) | Vz/F of AZD9291 | 1024 L |
| Fasted | Vz/F of AZD9291 | 1019 L |