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

Phase 1

Completed

Conditions: Non Small Cell Lung Cancer

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

Registration Number: NCT02197247

Lead Sponsor: AstraZeneca

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 41

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Rifampicin and AZD9291	Pharmacokinetic sampling - AZD9291	Sequential treatments of AZD9291 alone followed by AZD9291 +rifampicin, followed by AZD9291 alone.
Rifampicin and AZD9291	AZD9291 tablet dosing	Sequential treatments of AZD9291 alone followed by AZD9291 +rifampicin, followed by AZD9291 alone.
Rifampicin and AZD9291	Pharmacokinetic sampling - AZ5140 and AZ7550	Sequential treatments of AZD9291 alone followed by AZD9291 +rifampicin, followed by AZD9291 alone.
Rifampicin and AZD9291	Pharmacokinetic sampling - rifampicin	Sequential treatments of AZD9291 alone followed by AZD9291 +rifampicin, followed by AZD9291 alone.
Rifampicin and AZD9291	Rifampicin	Sequential treatments of AZD9291 alone followed by AZD9291 +rifampicin, followed by AZD9291 alone.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 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 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).
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 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 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 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,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 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 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 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 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 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 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).