Non Small Cell Lung Cancer
Conditions
Keywords
oncology, cancer, non small cell lung cancer, anticancer drug, pharmacokinetics, AZD9291, rifampicin, CYP P450 inducer, EGFR genes
Brief summary
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.
Interventions
PROCEDUREPharmacokinetic sampling - AZD9291
Blood sampling to measure AZD9291
DRUGRifampicin
Rifampicin (CYP inducer) 600mg taken once daily from Day 29 to Day 49 (Part A)
Part A: AZD9291 80mg tablet taken daily from Days 1 to 77. Part B: AZD9291 80mg tablet taken daily for 12 months.
PROCEDUREPharmacokinetic sampling - rifampicin
Blood sampling to measure rifampicin levels
Blood samples to measure levels of AZ5140 and AZ7550
Sponsors
AstraZeneca
Study design
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
For inclusion in the study patient should fulfil the following criteria: 1\. Male or female, aged at least 18 years. 2. Histological or cytological confirmation diagnosis of NSCLC. 3. 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. 4\. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5\. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G). 6\. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. 7\. 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 LH and 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. 8\. Male patients should be willing to use barrier contraception, ie, condoms, until 6 months after last study drug is taken. 9\. Contact lens wearers must be prepared to not wear contact lenses and wear glasses for the duration of the rifampicin dosing. 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 (eg, erlotinib or gefitinib) w/in 8 days or approx. 5 x half-life, whichever is the longer, of the first dose of study treatment; any cytotoxic chemo, investigational agents or other anticancer drugs from a previous treatment regimen w/in 14 days of the first dose of study treatment; major surgery (excluding placement of vascular access) w/in 4 weeks of the first 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 first; patients currently receiving (or unable to stop use prior to receiving the first dose) 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. 3. 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. 4. 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 78 of Part A. 5. Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment. 6. 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 HIV. Screening for chronic conditions is not required. 7. 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 the 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. 8. 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 electrocardiograms (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. 9. Patients unable to swallow oral medication or patients with GI disorders or significant GI 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 or rifampicin or any of the excipients of the products. 13. Concomitant medication contraindicated for use with rifampicin (including, but not limited to): cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide, triazolam, levacetylmethadol (levomethadyl), 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitors metabolised by CYP3A4, such as lovastatin and simvastatin, ergot alkaloids metabolised by CYP3A4, such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine). 14. 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 |
|---|---|---|
| Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max) | Samples collected on Day 28 following AZD9291 alone and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | 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). |
| Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau) | Samples collected on Day 28 following AZD9291 alone and Day 49 following AZD9291 and rifampicin at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Css,Max for AZ7550 (Metabolite) | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods). |
| Assessment of Css,Max for Rifampicin | Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2). |
| Assessment of AUCtau for AZD9291 Before and After Rifampicin | Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3). |
| Assessment of AUCtau for AZ5104 (Metabolite) | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods). |
| Assessment of AUCtau for AZ7550 (Metabolite) | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods). |
| Assessment of AUCtau for Rifampicin | Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2). |
| Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites) | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | 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). |
| Assessment of Css,Max for AZD9291 Before and After Rifampicin | Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | 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). |
| Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites) | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | 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). |
| Assessment of Css,Min for Rifampicin | Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | 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). |
| Assessment of CLss/F for AZD9291 | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | 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). |
| Assessment of CLss/F for Rifampicin | Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2). |
| Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max) | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | 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 Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau) | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | 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). |
| Assessment of Tss,Max for Rifampicin | Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2). |
| Assessment of Css,Max for AZ5104 (Metabolite) | Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A. | Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods). |
Countries
Netherlands, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
First patient enrolled: 04 December 2014; Last Subject Last Visit Part A: 09 July 2015 and Part B: 29 June 2016. Study performed at 18 sites across Asia, North America and Western Europe. Part A assessed effect of multiple doses of rifampicin on PK of AZD9291; Part B allowed subjects further access to AZD9291 and provided additional safety data.
Pre-assignment details
51 patients were enrolled (signed informed consent). Patients were assigned to treatment if they met all the inclusion and none of the exclusion criteria. 10 subjects were enrolled but failed inclusion/exclusion criteria and so were not eligible to be assigned treatment. The remaining 41 patients started Period 1 and received treatment.
Participants by arm
| Arm | Count |
|---|---|
| AZD9291 and Rifampicin (Part A); AZD9291 Alone (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. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Part A: Day 29-49 (AZD9291+Rifampicin) | Adverse Event | 2 |
| Part A: Day 29-49 (AZD9291+Rifampicin) | Condition under investigation worsened | 2 |
| Part A: Day 50-77 (AZD9291 Alone) | Condition under investigation worsened | 5 |
| Part B: Day 78 to End Part B (AZD9291) | Adverse Event | 2 |
| Part B: Day 78 to End Part B (AZD9291) | Condition under investigation worsened | 9 |
| Part B: Day 78 to End Part B (AZD9291) | Death | 1 |
| Part B: Day 78 to End Part B (AZD9291) | Newly discovered brain metastases | 1 |
| Part B: Day 78 to End Part B (AZD9291) | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | AZD9291 and Rifampicin (Part A); AZD9291 Alone (Part B) |
|---|---|
| Age, Continuous | 62.5 years STANDARD_DEVIATION 11.74 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 15 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 40 / 41 | 39 / 41 | 34 / 34 |
| serious Total, serious adverse events | 11 / 41 | 7 / 41 | 6 / 34 |
Outcome results
Primary
Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau)
Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).
Time frame: Samples collected on Day 28 following AZD9291 alone and Day 49 following AZD9291 and rifampicin at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau) | 10870 nM * hour (nM*h) | Geometric Coefficient of Variation 44.3 |
| AZD9291 + Rifampicin (Period 2) | Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau) | 2192 nM * hour (nM*h) | Geometric Coefficient of Variation 43.8 |
Comparison: 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.90% CI: [19.5, 23.83]
Primary
Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max)
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).
Time frame: Samples collected on Day 28 following AZD9291 alone and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max) | 577.4 nanomolar (nM) | Geometric Coefficient of Variation 44.7 |
| AZD9291 + Rifampicin (Period 2) | Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max) | 147.5 nanomolar (nM) | Geometric Coefficient of Variation 48.2 |
Comparison: 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.90% CI: [24.36, 30.29]
Secondary
Assessment of AUCtau for AZ5104 (Metabolite)
Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).
Time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of AUCtau for AZ5104 (Metabolite) | 1206 nM*h | Geometric Coefficient of Variation 55.8 |
| AZD9291 + Rifampicin (Period 2) | Assessment of AUCtau for AZ5104 (Metabolite) | 210.3 nM*h | Geometric Coefficient of Variation 48 |
| AZD9291 Alone (Period 3) | Assessment of AUCtau for AZ5104 (Metabolite) | 1029 nM*h | Geometric Coefficient of Variation 49.7 |
Comparison: 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.90% CI: [16.61, 21.19]
Comparison: 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.90% CI: [79.34, 102.27]
Secondary
Assessment of AUCtau for AZ7550 (Metabolite)
Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).
Time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of AUCtau for AZ7550 (Metabolite) | 1107 nM*h | Geometric Coefficient of Variation 41.7 |
| AZD9291 + Rifampicin (Period 2) | Assessment of AUCtau for AZ7550 (Metabolite) | 1416 nM*h | Geometric Coefficient of Variation 25.6 |
| AZD9291 Alone (Period 3) | Assessment of AUCtau for AZ7550 (Metabolite) | 1111 nM*h | Geometric Coefficient of Variation 31.7 |
Comparison: 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.90% CI: [119.14, 141.44]
Comparison: 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.90% CI: [92.15, 110.19]
Secondary
Assessment of AUCtau for AZD9291 Before and After Rifampicin
Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).
Time frame: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of AUCtau for AZD9291 Before and After Rifampicin | 10870 nM*h | Geometric Coefficient of Variation 44.3 |
| AZD9291 + Rifampicin (Period 2) | Assessment of AUCtau for AZD9291 Before and After Rifampicin | 10060 nM*h | Geometric Coefficient of Variation 36.8 |
Comparison: 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.90% CI: [86.37, 106.45]
Secondary
Assessment of AUCtau for Rifampicin
Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2).
Time frame: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of AUCtau for Rifampicin | 58610 ng*h/mL | Geometric Coefficient of Variation 36.8 |
Secondary
Assessment of CLss/F for AZD9291
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).
Time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of CLss/F for AZD9291 | 14.74 Litre per hour (L/h) | Geometric Coefficient of Variation 44.2 |
| AZD9291 + Rifampicin (Period 2) | Assessment of CLss/F for AZD9291 | 73.07 Litre per hour (L/h) | Geometric Coefficient of Variation 43.8 |
| AZD9291 Alone (Period 3) | Assessment of CLss/F for AZD9291 | 15.92 Litre per hour (L/h) | Geometric Coefficient of Variation 36.7 |
Secondary
Assessment of CLss/F for Rifampicin
Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2).
Time frame: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of CLss/F for Rifampicin | 10.23 L/h | Geometric Coefficient of Variation 36.7 |
Secondary
Assessment of Css,Max for AZ5104 (Metabolite)
Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).
Time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of Css,Max for AZ5104 (Metabolite) | 60.40 nM | Geometric Coefficient of Variation 57.2 |
| AZD9291 + Rifampicin (Period 2) | Assessment of Css,Max for AZ5104 (Metabolite) | 12.28 nM | Geometric Coefficient of Variation 52.6 |
| AZD9291 Alone (Period 3) | Assessment of Css,Max for AZ5104 (Metabolite) | 50.73 nM | Geometric Coefficient of Variation 49.8 |
Comparison: 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.90% CI: [19.08, 24.72]
Comparison: 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.90% CI: [77.17, 101.07]
Secondary
Assessment of Css,Max for AZ7550 (Metabolite)
Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).
Time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of Css,Max for AZ7550 (Metabolite) | 53.54 nM | Geometric Coefficient of Variation 43.7 |
| AZD9291 + Rifampicin (Period 2) | Assessment of Css,Max for AZ7550 (Metabolite) | 73.14 nM | Geometric Coefficient of Variation 25 |
| AZD9291 Alone (Period 3) | Assessment of Css,Max for AZ7550 (Metabolite) | 53.24 nM | Geometric Coefficient of Variation 34.4 |
Comparison: 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.90% CI: [127.74, 151.96]
Comparison: 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.90% CI: [92.04, 110.29]
Secondary
Assessment of Css,Max for AZD9291 Before and After Rifampicin
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).
Time frame: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of Css,Max for AZD9291 Before and After Rifampicin | 577.4 nM | Geometric Coefficient of Variation 44.7 |
| AZD9291 + Rifampicin (Period 2) | Assessment of Css,Max for AZD9291 Before and After Rifampicin | 531.4 nM | Geometric Coefficient of Variation 37.9 |
Comparison: 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.90% CI: [85.27, 107.03]
Secondary
Assessment of Css,Max for Rifampicin
Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2).
Time frame: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of Css,Max for Rifampicin | 13810 nanogram per millilitre (ng/mL) | Geometric Coefficient of Variation 40.6 |
Secondary
Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites)
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).
Time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZ7550 Css,min | 37.99 nM | Geometric Coefficient of Variation 44 |
| AZD9291 Alone (Period 1) | Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZD9291 Css,min | 354.7 nM | Geometric Coefficient of Variation 52.4 |
| AZD9291 Alone (Period 1) | Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZ5104 Css,min | 41.80 nM | Geometric Coefficient of Variation 62.1 |
| AZD9291 + Rifampicin (Period 2) | Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZ7550 Css,min | 44.89 nM | Geometric Coefficient of Variation 26.9 |
| AZD9291 + Rifampicin (Period 2) | Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZ5104 Css,min | 5.816 nM | Geometric Coefficient of Variation 51.6 |
| AZD9291 + Rifampicin (Period 2) | Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZD9291 Css,min | 50.56 nM | Geometric Coefficient of Variation 47.9 |
| AZD9291 Alone (Period 3) | Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZ5104 Css,min | 35.37 nM | Geometric Coefficient of Variation 51.4 |
| AZD9291 Alone (Period 3) | Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZ7550 Css,min | 37.68 nM | Geometric Coefficient of Variation 35.4 |
| AZD9291 Alone (Period 3) | Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZD9291 Css,min | 326.9 nM | Geometric Coefficient of Variation 41.1 |
Secondary
Assessment of Css,Min for Rifampicin
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).
Time frame: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of Css,Min for Rifampicin | NA ng/mL |
Secondary
Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau)
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).
Time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau) | AZ5104 AUCtau / AZD9291 AUCtau | 0.1109 Ratio | Geometric Coefficient of Variation 29 |
| AZD9291 Alone (Period 1) | Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau) | AZ7550 AUCtau / AZD9291 AUCtau | 0.1019 Ratio | Geometric Coefficient of Variation 52.3 |
| AZD9291 + Rifampicin (Period 2) | Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau) | AZ5104 AUCtau / AZD9291 AUCtau | 0.09595 Ratio | Geometric Coefficient of Variation 23.6 |
| AZD9291 + Rifampicin (Period 2) | Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau) | AZ7550 AUCtau / AZD9291 AUCtau | 0.6459 Ratio | Geometric Coefficient of Variation 28.2 |
| AZD9291 Alone (Period 3) | Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau) | AZ5104 AUCtau / AZD9291 AUCtau | 0.1023 Ratio | Geometric Coefficient of Variation 28.5 |
| AZD9291 Alone (Period 3) | Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau) | AZ7550 AUCtau / AZD9291 AUCtau | 0.1104 Ratio | Geometric Coefficient of Variation 38.8 |
Secondary
Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max)
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).
Time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max) | AZ5104 Css,max / AZD9291 Css,max | 0.1046 Ratio | Geometric Coefficient of Variation 31 |
| AZD9291 Alone (Period 1) | Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max) | AZ7550 Css,max / AZD9291 Css,max | 0.09276 Ratio | Geometric Coefficient of Variation 49.3 |
| AZD9291 + Rifampicin (Period 2) | Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max) | AZ5104 Css,max / AZD9291 Css,max | 0.08327 Ratio | Geometric Coefficient of Variation 27.4 |
| AZD9291 + Rifampicin (Period 2) | Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max) | AZ7550 Css,max / AZD9291 Css,max | 0.4960 Ratio | Geometric Coefficient of Variation 33.1 |
| AZD9291 Alone (Period 3) | Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max) | AZ5104 Css,max / AZD9291 Css,max | 0.09544 Ratio | Geometric Coefficient of Variation 27.4 |
| AZD9291 Alone (Period 3) | Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max) | AZ7550 Css,max / AZD9291 Css,max | 0.1002 Ratio | Geometric Coefficient of Variation 38.1 |
Secondary
Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites)
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).
Time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZD9291 tss,max | 4.97 h |
| AZD9291 Alone (Period 1) | Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZ7550 tss,max | 6.14 h |
| AZD9291 Alone (Period 1) | Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZ5104 tss,max | 6.00 h |
| AZD9291 + Rifampicin (Period 2) | Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZD9291 tss,max | 5.88 h |
| AZD9291 + Rifampicin (Period 2) | Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZ7550 tss,max | 7.95 h |
| AZD9291 + Rifampicin (Period 2) | Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZ5104 tss,max | 6.03 h |
| AZD9291 Alone (Period 3) | Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZ7550 tss,max | 7.03 h |
| AZD9291 Alone (Period 3) | Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZ5104 tss,max | 6.00 h |
| AZD9291 Alone (Period 3) | Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites) | AZD9291 tss,max | 6.00 h |
Secondary
Assessment of Tss,Max for Rifampicin
Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2).
Time frame: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD9291 Alone (Period 1) | Assessment of Tss,Max for Rifampicin | 2.00 h |