CClinicalTrials.gg
Sign In
CompletedNCT02197247Updated Jul 12, 2021Results posted

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

A Phase 1 interventional study of Pharmacokinetic sampling - AZD9291 and Rifampicin in Non Small Cell Lung Cancer, sponsored by AstraZeneca. Completed at 18 sites in 6 countries. Open to participants aged 18 Years to 130 Years. Per ClinicalTrials.gov, last updated 2021-07-12.

Sponsored by AstraZeneca · Phase 1, Interventional, and Other

Phase
Phase 1
Study type
Interventional
Enrollment
41
Ages
18 Years to 130 Years
Sex
All
01

Study 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.

02

Conditions studied

  • Non Small Cell Lung Cancer

Keywords

  • oncology, cancer, non small cell lung cancer, anticancer drug, pharmacokinetics, AZD9291, rifampicin, CYP P450 inducer, EGFR genes
03

In context

Carcinoma, Non-Small-Cell Lung

6,488 studies on the registry are indexed under Carcinoma, Non-Small-Cell Lung; 1,632 are open to participants now.

This study's enrollment of 41 is below the median of 62 across 5,213 interventional studies indexed under Carcinoma, Non-Small-Cell Lung.

Browse Carcinoma, Non-Small-Cell Lung studies →

Lead sponsor

AstraZeneca is the lead sponsor of 3,429 studies on the registry; 270 are open to participants now.

Of its 357 completed or terminated interventional studies of FDA-regulated products, 173 (48%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 130 Years
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility 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.
  1. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).
  1. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G).
  1. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening.
  1. 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.
  1. Male patients should be willing to use barrier contraception, ie, condoms, until 6 months after last study drug is taken.
  1. 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.
05

Study design

Phase
Phase 1
Primary purpose
Other
Masking
None (open label)
Enrollment
41 participants (actual)

Study arms

  • Experimental
    Rifampicin and AZD9291

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

    Procedure: Pharmacokinetic sampling - AZD9291 · Drug: Rifampicin · Drug: AZD9291 tablet dosing · Procedure: Pharmacokinetic sampling - rifampicin · Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550

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)

  • DrugAZD9291 tablet dosing

    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

  • ProcedurePharmacokinetic sampling - AZ5140 and AZ7550

    Blood samples to measure levels of AZ5140 and AZ7550

06

What researchers measure

Primary outcomes

  1. 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.

  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)

    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.

Secondary outcomes

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

07

Results

Posted Sep 28, 2016
Limitations and caveats
At end of Part B, the CAP allowed patients to continue receiving AZD9291 if still deriving clinical benefit. No clinical data was databased during the CAP; thus AE data is presented to end of Part B only.

Participant flow

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.

Part A: Day 1-28 (AZD9291 Alone)
Participant flow — Part A: Day 1-28 (AZD9291 Alone)
MilestoneAZD9291 and Rifampicin (Part A); AZD9291 Alone (Part B)
Started41
Completed41
Not completed0
Part A: Day 29-49 (AZD9291+Rifampicin)
Participant flow — Part A: Day 29-49 (AZD9291+Rifampicin)
MilestoneAZD9291 and Rifampicin (Part A); AZD9291 Alone (Part B)
Started41
Completed37
Not completed4
Withdrew: Adverse event2
Withdrew: Condition under investigation worsened2
Part A: Day 50-77 (AZD9291 Alone)
Participant flow — Part A: Day 50-77 (AZD9291 Alone)
MilestoneAZD9291 and Rifampicin (Part A); AZD9291 Alone (Part B)
Started37
Completed32
Not completed5
Withdrew: Condition under investigation worsened5
Part B: Day 78 to End Part B (AZD9291)
Participant flow — Part B: Day 78 to End Part B (AZD9291)
MilestoneAZD9291 and Rifampicin (Part A); AZD9291 Alone (Part B)
Started34
Completed19
Not completed15
Withdrew: Adverse event2
Withdrew: Withdrawal by subject2
Withdrew: Newly discovered brain metastases1
Withdrew: Death1
Withdrew: Condition under investigation worsened9

Outcome measures

PrimaryAssessment 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.
Reported as:
Geometric mean · nanomolar (nM)
Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max)
nanomolar (nM)AZD9291 Alone (Period 1)AZD9291 + Rifampicin (Period 2)
Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max)577.4 ± 44.7147.5 ± 48.2
Statistical analysis
  • AZD9291 Alone (Period 1) vs AZD9291 + Rifampicin (Period 2) · Geometric least-squares (ls) mean ratio: 27.16 · 90% CI 24.36 to 30.29AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1).
PrimaryAssessment 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.
Reported as:
Geometric mean · nM * hour (nM*h)
Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau)
nM * hour (nM*h)AZD9291 Alone (Period 1)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)10870 ± 44.32192 ± 43.8
Statistical analysis
  • AZD9291 Alone (Period 1) vs AZD9291 + Rifampicin (Period 2) · Geometric ls mean ratio: 21.55 · 90% CI 19.50 to 23.83AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1).
SecondaryAssessment 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.
Reported as:
Geometric mean · nM
Assessment of Css,Max for AZD9291 Before and After Rifampicin
nMAZD9291 Alone (Period 1)AZD9291 Alone (Period 3)
Assessment of Css,Max for AZD9291 Before and After Rifampicin577.4 ± 44.7531.4 ± 37.9
Statistical analysis
  • AZD9291 Alone (Period 1) vs AZD9291 Alone (Period 3) · Geometric ls mean ratio: 95.53 · 90% CI 85.27 to 107.03AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for AZD9291 alone in separate periods, but analysed for consistency with AZD9291+rifampicin / AZD9291 alone analysis (primary outcome measure).
SecondaryAssessment 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.
Reported as:
Geometric mean · nM
Assessment of Css,Max for AZ5104 (Metabolite)
nMAZD9291 Alone (Period 1)AZD9291 + Rifampicin (Period 2)AZD9291 Alone (Period 3)
Assessment of Css,Max for AZ5104 (Metabolite)60.40 ± 57.212.28 ± 52.650.73 ± 49.8
Statistical analysis
  • AZD9291 Alone (Period 1) vs AZD9291 + Rifampicin (Period 2) · Geometric ls mean ratio: 21.72 · 90% CI 19.08 to 24.72AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.
  • AZD9291 Alone (Period 1) vs AZD9291 Alone (Period 3) · Geometric ls mean ratio: 88.31 · 90% CI 77.17 to 101.07AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.
SecondaryAssessment 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.
Reported as:
Geometric mean · nM
Assessment of Css,Max for AZ7550 (Metabolite)
nMAZD9291 Alone (Period 1)AZD9291 + Rifampicin (Period 2)AZD9291 Alone (Period 3)
Assessment of Css,Max for AZ7550 (Metabolite)53.54 ± 43.773.14 ± 25.053.24 ± 34.4
Statistical analysis
  • AZD9291 Alone (Period 1) vs AZD9291 + Rifampicin (Period 2) · Geometric ls mean ratio: 139.32 · 90% CI 127.74 to 151.96AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.
  • AZD9291 Alone (Period 1) vs AZD9291 Alone (Period 3) · Geometric ls mean ratio: 100.75 · 90% CI 92.04 to 110.29AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.
SecondaryAssessment 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.
Reported as:
Geometric mean · nanogram per millilitre (ng/mL)
Assessment of Css,Max for Rifampicin
nanogram per millilitre (ng/mL)AZD9291 + Rifampicin (Period 2)
Assessment of Css,Max for Rifampicin13810 ± 40.6
SecondaryAssessment 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.
Reported as:
Geometric mean · nM*h
Assessment of AUCtau for AZD9291 Before and After Rifampicin
nM*hAZD9291 Alone (Period 1)AZD9291 Alone (Period 3)
Assessment of AUCtau for AZD9291 Before and After Rifampicin10870 ± 44.310060 ± 36.8
Statistical analysis
  • AZD9291 Alone (Period 1) vs AZD9291 Alone (Period 3) · Geometric ls mean ratio: 95.89 · 90% CI 86.37 to 106.45AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for AZD9291 alone in separate periods, but analysed for consistency with AZD9291+rifampicin / AZD9291 alone analysis (primary outcome measure).
SecondaryAssessment 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.
Reported as:
Geometric mean · nM*h
Assessment of AUCtau for AZ5104 (Metabolite)
nM*hAZD9291 Alone (Period 1)AZD9291 + Rifampicin (Period 2)AZD9291 Alone (Period 3)
Assessment of AUCtau for AZ5104 (Metabolite)1206 ± 55.8210.3 ± 48.01029 ± 49.7
Statistical analysis
  • AZD9291 Alone (Period 1) vs AZD9291 + Rifampicin (Period 2) · Geometric ls mean ratio: 18.76 · 90% CI 16.61 to 21.19AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.
  • AZD9291 Alone (Period 1) vs AZD9291 Alone (Period 3) · Geometric ls mean ratio: 90.08 · 90% CI 79.34 to 102.27AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.
SecondaryAssessment 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.
Reported as:
Geometric mean · nM*h
Assessment of AUCtau for AZ7550 (Metabolite)
nM*hAZD9291 Alone (Period 1)AZD9291 + Rifampicin (Period 2)AZD9291 Alone (Period 3)
Assessment of AUCtau for AZ7550 (Metabolite)1107 ± 41.71416 ± 25.61111 ± 31.7
Statistical analysis
  • AZD9291 Alone (Period 1) vs AZD9291 + Rifampicin (Period 2) · Geometric ls mean ratio: 129.81 · 90% CI 119.14 to 141.44AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.
  • AZD9291 Alone (Period 1) vs AZD9291 Alone (Period 3) · Geometric ls mean ratio: 100.76 · 90% CI 92.15 to 110.19AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.
SecondaryAssessment 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.
Reported as:
Geometric mean · ng*h/mL
Assessment of AUCtau for Rifampicin
ng*h/mLAZD9291 + Rifampicin (Period 2)
Assessment of AUCtau for Rifampicin58610 ± 36.8
SecondaryAssessment 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.
Reported as:
Median · h
Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites)
hAZD9291 Alone (Period 1)AZD9291 + Rifampicin (Period 2)AZD9291 Alone (Period 3)
AZD9291 tss,max4.97 (2.88 to 9.88)5.88 (3.00 to 10.00)6.00 (3.17 to 23.92)
AZ5104 tss,max6.00 (0.00 to 24.00)6.03 (3.00 to 11.43)6.00 (0.00 to 24.00)
AZ7550 tss,max6.14 (2.88 to 24.92)7.95 (4.00 to 12.00)7.03 (1.10 to 24.00)
SecondaryAssessment 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.
Reported as:
Median · h
Assessment of Tss,Max for Rifampicin
hAZD9291 + Rifampicin (Period 2)
Assessment of Tss,Max for Rifampicin2.00 (0.83 to 6.07)
SecondaryAssessment 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.
Reported as:
Geometric mean · nM
Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites)
nMAZD9291 Alone (Period 1)AZD9291 + Rifampicin (Period 2)AZD9291 Alone (Period 3)
AZD9291 Css,min354.7 ± 52.450.56 ± 47.9326.9 ± 41.1
AZ5104 Css,min41.80 ± 62.15.816 ± 51.635.37 ± 51.4
AZ7550 Css,min37.99 ± 44.044.89 ± 26.937.68 ± 35.4
SecondaryAssessment 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.
Reported as:
Geometric mean · ng/mL
Assessment of Css,Min for Rifampicin
ng/mLAZD9291 + Rifampicin (Period 2)
Assessment of Css,Min for RifampicinNA ± NA
SecondaryAssessment 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.
Reported as:
Geometric mean · Litre per hour (L/h)
Assessment of CLss/F for AZD9291
Litre per hour (L/h)AZD9291 Alone (Period 1)AZD9291 + Rifampicin (Period 2)AZD9291 Alone (Period 3)
Assessment of CLss/F for AZD929114.74 ± 44.273.07 ± 43.815.92 ± 36.7
SecondaryAssessment 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.
Reported as:
Geometric mean · L/h
Assessment of CLss/F for Rifampicin
L/hAZD9291 + Rifampicin (Period 2)
Assessment of CLss/F for Rifampicin10.23 ± 36.7
SecondaryAssessment 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.
Reported as:
Geometric mean · Ratio
Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max)
RatioAZD9291 Alone (Period 1)AZD9291 + Rifampicin (Period 2)AZD9291 Alone (Period 3)
AZ5104 Css,max / AZD9291 Css,max0.1046 ± 31.00.08327 ± 27.40.09544 ± 27.4
AZ7550 Css,max / AZD9291 Css,max0.09276 ± 49.30.4960 ± 33.10.1002 ± 38.1
SecondaryAssessment 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.
Reported as:
Geometric mean · Ratio
Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau)
RatioAZD9291 Alone (Period 1)AZD9291 + Rifampicin (Period 2)AZD9291 Alone (Period 3)
AZ5104 AUCtau / AZD9291 AUCtau0.1109 ± 29.00.09595 ± 23.60.1023 ± 28.5
AZ7550 AUCtau / AZD9291 AUCtau0.1019 ± 52.30.6459 ± 28.20.1104 ± 38.8

Adverse events

Collected over Approximately 3 months for Part A; up to approximately 14 months for Part B and approximately 17 months for Overall (Parts A and B combined).. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Overall—11/41 (26.8%)40/41 (97.6%)
Part A—7/41 (17.1%)39/41 (95.1%)
Part B—6/34 (17.6%)34/34 (100%)
Most frequent serious events
Showing 10 of 13
Most frequent serious events
EventOverallPart APart B
InfluenzaInfections and infestations2/411/411/34
Atrial fibrillationCardiac disorders1/410/411/34
IleusGastrointestinal disorders1/410/411/34
Hepatitis BInfections and infestations1/410/411/34
PneumoniaInfections and infestations1/410/411/34
Pulmonary sepsisInfections and infestations1/410/411/34
Thrombotic strokeNervous system disorders1/410/411/34
Cardiac failure congestiveCardiac disorders1/411/410/34
MalaiseGeneral disorders1/411/410/34
Femur fractureInjury, poisoning and procedural complications1/411/410/34
Most frequent other events
Showing 10 of 57
Most frequent other events
EventOverallPart APart B
DiarrhoeaGastrointestinal disorders22/4114/4114/34
Decreased appetiteMetabolism and nutrition disorders19/416/4113/34
Dry skinSkin and subcutaneous tissue disorders17/4110/4112/34
NauseaGastrointestinal disorders13/418/419/34
FatigueGeneral disorders13/418/415/34
VomitingGastrointestinal disorders11/415/417/34
Back painMusculoskeletal and connective tissue disorders11/416/415/34
StomatitisGastrointestinal disorders10/416/416/34
CoughRespiratory, thoracic and mediastinal disorders10/417/414/34
Musculoskeletal painMusculoskeletal and connective tissue disorders9/414/415/34

Baseline characteristics

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

Age, Continuous
Age, Continuous(years)AZD9291 and Rifampicin (Part A); AZD9291 Alone (Part B)
Mean62.5 ± 11.74
Sex: Female, Male
Sex: Female, Male(Participants)AZD9291 and Rifampicin (Part A); AZD9291 Alone (Part B)
Female32
Male9
Race (NIH/OMB)
Race (NIH/OMB)(Participants)AZD9291 and Rifampicin (Part A); AZD9291 Alone (Part B)
American Indian or Alaska Native0
Asian15
Native Hawaiian or Other Pacific Islander0
Black or African American2
White24
More than one race0
Unknown or Not Reported0
08

Study locations

18 sites
  • Research Site
    Atlanta, Georgia 30322, United States
  • Research Site
    Detroit, Michigan 48202, United States
  • Research Site
    Seongnam-si, 13620, Korea, Republic of
  • Research Site
    Seoul, 03722, Korea, Republic of
  • Research Site
    Seoul, 06351, Korea, Republic of
  • Research Site
    Amsterdam, 1066 CX, Netherlands
  • Research Site
    Maastricht, 6229 HX, Netherlands
  • Research Site
    Barcelona, 08041, Spain
  • Research Site
    L'Hospitalet de Llobregat, 08908, Spain
  • Research Site
    Madrid, 28040, Spain
  • Research Site
    Madrid, 28041, Spain
  • Research Site
    Madrid, 28046, Spain
  • Research Site
    Málaga, 29010, Spain
  • Research Site
    Sevilla, 41013, Spain
  • Research Site
    Taipei, 10002, Taiwan
  • Research Site
    Taipei, 112, Taiwan
  • Research Site
    Cardiff, CF14 2TL, United Kingdom
  • Research Site
    Manchester, M20 4BX, United Kingdom
09

References and documents

Publications

  • Vishwanathan K, Dickinson PA, So K, Thomas K, Chen YM, De Castro Carpeno J, Dingemans AC, Kim HR, Kim JH, Krebs MG, Chih-Hsin Yang J, Bui K, Weilert D, Harvey RD. The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib. Br J Clin Pharmacol. 2018 Jun;84(6):1156-1169. doi: 10.1111/bcp.13534. Epub 2018 Mar 23. PubMed 29381826 ↗

Individual participant data

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

Supporting information: Study protocol, Sap

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jul 12, 2021, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02197247
Lead sponsor
AstraZeneca
Responsible party
Sponsor
First posted
Jul 22, 2014
Start date
Dec 4, 2014
Primary completion
Jul 9, 2015
Completion
May 26, 2021
Results posted
Sep 28, 2016
Last update
Jul 12, 2021

Study contacts

Serban Ghiorghiu, MSD
study director · AstraZeneca

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Jun 2021. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Carcinoma, Non-Small-Cell Lung→

Other studies from this sponsor

AstraZeneca

Start the discussion