The purpose of this study is to determine the safety, tolerability and preliminary anti-tumour activity of AZD9291 when given together with AZD6094 or selumetinib in patients with EGFR mutation positive advanced lung cancer.
Name: Part A - AZD9291 in combination with AZD6094
Name: Part A - AZD9291 in combination with continuous selumetinib (Asian subjects)
Name: Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects)
Name: Part A - AZD9291 in combination with intermittent selumetinib
Name: Part A - AZD9291 in combination with MEDI4736
Name: Part B - AZD9291 in combination with AZD6094
Name: Part B - AZD9291 in combination with selumetinib
Name: Part B - AZD9291 in combination with MEDI4736
Name: Part C - AZD6094 monotherapy (Japan only)
Name: Part C - AZD9291 in combination with AZD6094 (Japan only)
Name: Part D - AZD9291 in combination with AZD6094
Description: Part A: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation.
Measure: Number of participants with Adverse Events and/or Dose Limiting Toxicities as a Measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib Time: Adverse events will be collected from baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.Description: Part B: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib in patients with locally advanced or metastatic NSCLC, who have progressed on prior therapy with an EGFR TKI agent. Part C monotherapy cohort (Japan only): To investigate and confirm the safety and tolerability of AZD6094 when given orally to Japanese patients with advanced solid malignancies. Part C combination cohort (Japan only): To investigate the safety and tolerability of AZD9291 when given orally to Japanese patients with EGFRm+ NSCLC in combination with AZD6094 who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation. Part D: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 (300 mg OD) in patients with locally advanced or metastatic EGFRm+ NSCLC.
Measure: Number of participants with Adverse Events as a measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib Time: Adverse events: baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: Cmax after single dosing Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hoursDescription: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: Tmax after single dosing Time: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hoursDescription: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: AUC after single dosing Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hoursDescription: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: AUC0-t after single dosing Time: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hoursDescription: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: AUC0-24 after single dosing Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hoursDescription: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: Terminal half life after single dosing Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hoursDescription: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: CL/f after single dosing Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hoursDescription: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: Volume of distribution after single dosing Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hoursDescription: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: Cssmax after multiple dosing Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hoursDescription: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: Tssmax after multiple dosing Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hoursDescription: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: Cssmin after multiple dosing Time: Blood samples will be collected from each subject at pre-specified times for the duration of treatment.Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: AUCss after multiple dosing Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hoursDescription: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: CLss/f after multiple dosing Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hoursDescription: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: Rac after multiple dosing Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: Time dependency of PK after multiple dosing Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1.
Measure: Objective response rate Time: At baseline and every 6 weeks until disease progression or withdrawal from study.Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1
Measure: Disease control rate Time: At baseline and every 6 weeks until disease progression or withdrawal from study.Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1
Measure: Duration of response Time: At baseline and every 6 weeks until disease progression or withdrawal from study.Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1
Measure: Percentage change in tumour size Time: At baseline and every 6 weeks until disease progression or withdrawal from study.Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1 Expansion phase only
Measure: Progression free survival Time: At baseline and every 6 weeks until disease progression or withdrawal from study.Description: To obtain a preliminary assessment of overall survival in the AZD9291+AZD6094 combination arms of the study for Parts B and D.
Measure: Overall survival Time: Confirmed during the FUP period and at least every 12 weeks until the data cut-off for the primary analysis and determination that no further OS collection is needed, approximately 5 years, death, or full withdrawal of consent, whichever comes first.Allocation: Non-Randomized
Parallel Assignment
There are 2 SNPs
Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including exon 19 deletion and L858R). --- L858R ---
Local confirmation of tumour T790M status is acceptable if performed with an approved test and agreed by AstraZeneca. --- T790M ---
Prior treatment with a 3rd generation (T790M-directed) therapy (eg, AZD9291, rociletinib or HM61713) outside of this study is permitted if allocated to the 3rd generation EGFR TKI cohort. --- T790M ---