AZD9291 in Combination With Ascending Doses of Novel Therapeutics

Phase 1

Active, not recruiting

• Conditions: Advanced Non Small Cell Lung Cancer
• Interventions: Drug: Part A - AZD9291 in combination with AZD6094; Drug: Part A - AZD9291 in combination with continuous selumetinib (Asian subjects); Drug: Part A - AZD9291 in combination with MEDI4736; Drug: Part C - AZD6094 monotherapy (Japan only); Drug: Part B - AZD9291 in combination with AZD6094; Drug: Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects); Drug: Part B - AZD9291 in combination with MEDI4736; Drug: Part C - AZD9291 in combination with AZD6094 (Japan only); Drug: Part A - AZD9291 in combination with intermittent selumetinib; Drug: Part D - AZD9291 in combination with AZD6094; Drug: Part B - AZD9291 in combination with selumetinib

• Registration Number: NCT02143466
• Lead Sponsor: AstraZeneca

Brief Summary

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

Detailed Description

This is a Phase Ib, open-label, multicentre study of AZD9291 administered orally in combination with novel therapeutics (AZD6094 or selumetinib (AZD6244, ARRY142886)) to patients with EGFRm+ advanced NSCLC. The study has been designed to allow an investigation of the optimal combination dose and schedule whilst ensuring the safety of patients with intensive safety monitoring. There are three main parts to this study; Part A, Combination dose finding and Parts B and D, Dose expansion. Part C, AZD6094 dose finding sub-study in advanced solid tumour patients is ongoing in Japan.

AZD9291 (osimertinib) is a potent irreversible inhibitor of both the single epidermal growth factor receptor sensitising mutation positive (EGFRm+) (tyrosine kinase inhibitor \[TKI\] sensitivity-conferring mutation) and dual EGFRm+/T790M+ (TKI resistance-conferring mutation) receptor forms of EGFR. AZD9291 therefore has the potential to provide clinical benefit to patients with advanced non-small cell lung cancer (NSCLC) harbouring both the single sensitivity mutations and the resistance mutation following prior therapy with an EGFR TKI. AZD9291 (osimertinib) was awarded FDA accelerated approval in November 2015, followed by conditional approval in the EU, full approval in Japan and additional markets in 2016, for the treatment of patients with EGFR T790M+ NSCLC who have progressed on or after EGFR TKI therapy.

Enrolment into the patient cohort that evaluated AZD9291 treatment in combination with MEDI4736 as 1st line treatment has been terminated due to an increased incidence of ILD-like events (interstitial lung disease/pneumonitis), and is no longer being evaluated in this study.

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Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations
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Related News

Study Timeline

• Study First Submitted: 2014-05-09
• Study First Submitted QC: 2014-05-19
• Study First Posted: 2014-05-21
• Study Start: 2014-08-05
• Primary Completion: 2020-03-04
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-27
• Last Update Posted: 2024-11-29
• Study Completion: 2024-12-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 344

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
AZD6094	Part A - AZD9291 in combination with AZD6094	AZD9291 in combination with AZD6094
AZD6094	Part B - AZD9291 in combination with AZD6094	AZD9291 in combination with AZD6094
AZD6094	Part C - AZD9291 in combination with AZD6094 (Japan only)	AZD9291 in combination with AZD6094
AZD6094	Part D - AZD9291 in combination with AZD6094	AZD9291 in combination with AZD6094
Selumetinib	Part A - AZD9291 in combination with continuous selumetinib (Asian subjects)	AZD9291 in combination with selumetinib
Selumetinib	Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects)	AZD9291 in combination with selumetinib
Selumetinib	Part A - AZD9291 in combination with intermittent selumetinib	AZD9291 in combination with selumetinib
Selumetinib	Part B - AZD9291 in combination with selumetinib	AZD9291 in combination with selumetinib
MEDI4736	Part A - AZD9291 in combination with MEDI4736	AZD9291 in combination with MEDI4736. Enrolment into the patient cohort that evaluated AZD9291 treatment in combination with MEDI4736 as 1st line treatment has been terminated due to an increased incidence of ILD-like events (interstitial lung disease/pneumonitis), and is no longer being evaluated in this study.
MEDI4736	Part B - AZD9291 in combination with MEDI4736	AZD9291 in combination with MEDI4736. Enrolment into the patient cohort that evaluated AZD9291 treatment in combination with MEDI4736 as 1st line treatment has been terminated due to an increased incidence of ILD-like events (interstitial lung disease/pneumonitis), and is no longer being evaluated in this study.
AZD6094 (monotherapy)	Part C - AZD6094 monotherapy (Japan only)	AZD6094 in monotherapy (for Japan only)

Primary Outcome Measures

Name	Time	Method
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	Adverse events will be collected from baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.	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.
Number of participants with Adverse Events as a measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib	Adverse events: baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.	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.

Secondary Outcome Measures

Name	Time	Method
CL/f after single dosing	Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours	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.
Volume of distribution after single dosing	Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours	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.
Cssmax after multiple dosing	Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours	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.
Tssmax after multiple dosing	Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours	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.
Cssmin after multiple dosing	Blood samples will be collected from each subject at pre-specified times for the duration of treatment.	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.
AUCss after multiple dosing	Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours	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.
CLss/f after multiple dosing	Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours	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.
AUC0-24 after single dosing	Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours	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.
Rac after multiple dosing	Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1	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.
Time dependency of PK after multiple dosing	Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1	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.
Objective response rate	At baseline and every 6 weeks until disease progression or withdrawal from study.	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.
Disease control rate	At baseline and every 6 weeks until disease progression or withdrawal from study.	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
Duration of response	At baseline and every 6 weeks until disease progression or withdrawal from study.	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
Terminal half life after single dosing	Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours	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.
Percentage change in tumour size	At baseline and every 6 weeks until disease progression or withdrawal from study.	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
Progression free survival	At baseline and every 6 weeks until disease progression or withdrawal from study.	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
Overall survival	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.	To obtain a preliminary assessment of overall survival in the AZD9291+AZD6094 combination arms of the study for Parts B and D.
Cmax after single dosing	Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours	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.
Tmax after single dosing	Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours	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.
AUC after single dosing	Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours	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.
AUC0-t after single dosing	Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours	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.

Trial Locations

Locations (1)

Research Site; 🇺🇦 Vinnytsia, Ukraine