AURA2: Phase II AZD9291 Open Label Study in NSCLC After Previous EGFR TKI Therapy in EGFR and T790M Mutation Positive Tumours

• Sponsor: AstraZeneca (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02094261
• Collaborator: (none)
• Enrollment: 210
• Locations: 44
• Arm: 1
• Anticipated Duration (Months): 103.4
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive

Condition or Disease	Intervention/Treatment	Phase
Non Small Cell Lung Cancer	Drug: AZD9291	Phase 2

Detailed Description

This is a phase II, open label, single arm study assessing the safety and efficacy of AZD9291 (80 mg, orally, once daily) in patients with a confirmed diagnosis of Epidermal Growth Factor Receptor mutation positive and T790M mutation positive NSCLC,who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent. Patients must agree to provide a biopsy for central confirmation of T790M mutation status following confirmed disease progression on the most recent treatment regimen. The primary objective of the study is to assess the efficacy of AZD9291 by assessment of Objective Response Rate according to RECIST 1.1 by an Independent Central Review.

Study Design

• Study Type: Interventional
• Actual Enrollment: 210 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II, Open Label, Single-arm Study to Assess Safety and Efficacy of AZD9291 in Patients With Locally Advanced/Metastatic NSCLC Whose Disease Has Progressed With Previous EGFR TKI and Whose Tumours Are EGFR and T790M Mutation Positive
• Actual Study Start Date: May 20, 2014
• Actual Primary Completion Date: May 1, 2015
• Anticipated Study Completion Date: Dec 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AZD9291 Once daily tablet 80 mg	Drug: AZD9291; Once daily tablet 80 mg

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR) [RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)]

   Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Secondary Outcome Measures

1. Duration of Response (DoR) [RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)]

   Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).

2. Disease Control Rate (DCR) [RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)]

   Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

3. Progression-Free Survival (PFS) [RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)]

   Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion:

• Aged at least 18 years. Japan patients aged at least 20 years.

• Locally advanced/metastatic NSCLC not amenable to curative surgery or radiotherapy

• Radiological documentation of disease progression:

following 1st line EGFR TKI treatment but who have not received further treatment OR following prior therapy with an EGFR TKI and a platinum-based doublet chemotherapy. Patients who received prior EGFR TKI and platinum-based doublet chemotherapy may have also received additional lines of treatment. All patients must have documented radiological progression on the last treatment administered prior to enrolling in the study.

• Disease progression following 1st line EGFR TKI treatment or following prior EGFR TKI and platinum-containing doublet chemotherapy.

• Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). Patients must have central confirmation of tumour T790M mutation positive status from a biopsy sample taken after confirmation of disease progression on the most recent treatment regimen.

• World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.

• At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm) with computerised tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements.

• Females of child-bearing potential using contraception; negative pregnancy test.

Exclusion:

• Treatment with an EGFR-TKI within 8 days of study entry; any cytotoxic chemotherapy, investigational agents or other anticancer drugs within 14 days of study entry; previous treatment with AZD9291 (or 3rd generation TKIs); major surgery within 4 weeks; radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks; current treatment with potent inhibitors of CYP2C8 and potent inhibitors/inducers of CYP3A4.

• Unresolved toxicities from prior therapy.

• Unstable spinal cord compression/brain metastases.

• Severe/uncontrolled systemic diseases, including uncontrolled hypertension, bleeding diatheses or infection.

• Refractory nausea/vomiting, chronic gastrointestinal diseases or bowel resection.

• Cardiac disease.

• Past history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.

• Inadequate bone marrow reserve or organ function.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	La Jolla	California	United States	92093
2	Research Site	Orange	California	United States	92868
3	Research Site	New Haven	Connecticut	United States	06510
4	Research Site	Norwalk	Connecticut	United States	06850
5	Research Site	Indianapolis	Indiana	United States	46202
6	Research Site	Boston	Massachusetts	United States	02215
7	Research Site	Lebanon	New Hampshire	United States	03756
8	Research Site	New York	New York	United States	10032
9	Research Site	Durham	North Carolina	United States	27710
10	Research Site	Edmonton	Alberta	Canada	T6G 1Z2
11	Research Site	Ottawa	Ontario	Canada	K1H 8L6
12	Research Site	Toronto	Ontario	Canada	M5G 2M9
13	Research Site	Hong Kong		Hong Kong
14	Research Site	Shatin		Hong Kong	00000
15	Research Site	Milano		Italy	20132
16	Research Site	Milan		Italy	20141
17	Research Site	Napoli		Italy	80131
18	Research Site	Perugia		Italy	06132
19	Research Site	Verona		Italy	37134
20	Research Site	Akashi-shi		Japan	673-8558
21	Research Site	Chuo-ku		Japan	104-0045
22	Research Site	Kitaadachi-gun		Japan	362-0806
23	Research Site	Kitakyushu-shi		Japan	802-0077
24	Research Site	Koto-ku		Japan	135-8550
25	Research Site	Nagoya-shi		Japan	460-0001
26	Research Site	Nagoya-shi		Japan	464-8681
27	Research Site	Niigata-shi		Japan	951-8566
28	Research Site	Osaka-shi		Japan	534-0021
29	Research Site	Osaka-shi		Japan	541-8567
30	Research Site	Osakasayama		Japan	589-8511
31	Research Site	Sakai-shi		Japan	591-8555
32	Research Site	Wakayama-shi		Japan	641-8510
33	Research Site	Yokohama-shi		Japan	236-0051
34	Research Site	Goyang-si		Korea, Republic of	10408
35	Research Site	Seongnam-si		Korea, Republic of	13620
36	Research Site	Seoul		Korea, Republic of	06591
37	Research Site	A Coruña		Spain	15006
38	Research Site	Barcelona		Spain	08025
39	Research Site	Madrid		Spain	28007
40	Research Site	Majadahonda		Spain	28222
41	Research Site	Málaga		Spain	29010
42	Research Site	Valencia		Spain	46026
43	Research Site	Taichung		Taiwan	40705
44	Research Site	Taipei		Taiwan	112

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Glenwood Goss, MD, 501 Smyth Road, Ottawa, Canada
• Principal Investigator: Tetsuya Mitsudomi, MD, Kinki University Hospital, Faculty of Medicine, Osaka, Japan

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• D5160C00002_12_1_01csp_andamendments-redaction_proposal_Redacted1

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02094261
• Other Study ID Numbers: D5160C00002
• First Posted: Mar 21, 2014
• Last Update Posted: Jun 6, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by AstraZeneca: Phase II, open label study; safety and efficacy of AZD9291; diagnosis of Epidermal Growth Factor Receptor mutation positive and T790M mutation positive NSCLC
• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung; Osimertinib

Study Results

Participant Flow

Recruitment Details	First patient enrolled: 28 April 2014, Data cut off: 1 May 2015. The study was open for enrolment at 44 study centres in Canada (3), Hong Kong (2), Italy (5), Japan (14), South Korea (3), Spain (6), Taiwan (2), and the USA (9). Recruitment has closed and primary analyses have been performed but study is still on-going.
Pre-assignment Detail	472 patients were enrolled (signed informed consent). Patients were assigned to treatment if they met all the inclusion and none of the exclusion criteria. 262 patients were enrolled but failed inclusion/exclusion criteria and so were not eligible to be assigned treatment. The remaining 210 patients received treatment.

Arm/Group Title	AZD9291 80mg
Arm/Group Description	Daily single dose of AZD9291 80mg
Period Title: Overall Study
STARTED	210
COMPLETED	0
NOT COMPLETED	210

Baseline Characteristics

Arm/Group Title	AZD9291 80mg
Arm/Group Description	Daily single dose of AZD9291 80mg
Overall Participants	210
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.9 (10.91)
Age, Customized (Number) [Number]
<50 Years	20 9.5%
>=50-<65 Years	88 41.9%
>=65-<75 Years	69 32.9%
>=75 Years	33 15.7%
Sex: Female, Male (Count of Participants)
Female	146 69.5%
Male	64 30.5%
Race/Ethnicity, Customized (Number) [Number]
Asian	132 62.9%
Black Or African American	3 1.4%
Native Hawaiian Or Other Pacific Islander	1 0.5%
Other	2 1%
White	72 34.3%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR)
Description	Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.
Time Frame	RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Outcome Measure Data

Analysis Population Description

All patients who received at least 1 dose of study treatment and had measurable disease at baseline according to the independent review of baseline imaging data.

Arm/Group Title	AZD9291 80mg
Arm/Group Description	Daily single dose of AZD9291 80mg
Measure Participants	199
Number (95% Confidence Interval) [% of participants]	70.9 33.8%

2. Secondary Outcome

Title	Duration of Response (DoR)
Description	Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).
Time Frame	RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Outcome Measure Data

Analysis Population Description

All patients who received at least 1 dose of study treatment, had measurable disease at baseline according to the independent review of baseline imaging data and had confirmed response.

Arm/Group Title	AZD9291 80mg
Arm/Group Description	Daily single dose of AZD9291 80mg
Measure Participants	141
Median (Full Range) [months]	7.8

3. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.
Time Frame	RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Outcome Measure Data

Analysis Population Description

All patients who received at least 1 dose of study treatment and had measurable disease at baseline according to the independent review of baseline imaging data.

Arm/Group Title	AZD9291 80mg
Arm/Group Description	Daily single dose of AZD9291 80mg
Measure Participants	199
Number (95% Confidence Interval) [% of participants]	91.5 43.6%

4. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.
Time Frame	RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Outcome Measure Data

Analysis Population Description

All patients who received at least 1 dose of study treatment.

Arm/Group Title	AZD9291 80mg
Arm/Group Description	Daily single dose of AZD9291 80mg
Measure Participants	210
Median (95% Confidence Interval) [months]	8.6

Adverse Events

Time Frame	AEs from start of study drug until 28 days post treatment discontinuation, up to approximately 11 months (at time of analysis).
Adverse Event Reporting Description	Systematic assessment due to regular investigator assessment at study visits.
Arm/Group Title	AZD9291 80mg
Arm/Group Description	Daily single dose of AZD9291 80mg
All Cause Mortality
	AZD9291 80mg
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	AZD9291 80mg
	Affected / at Risk (%)	# Events
Total	42/210 (20%)
Blood and lymphatic system disorders
Anaemia	1/210 (0.5%)	1
Thrombocytopenia	1/210 (0.5%)	1
Cardiac disorders
Supraventricular tachycardia	2/210 (1%)	2
Ear and labyrinth disorders
Hearing impaired	1/210 (0.5%)	1
Gastrointestinal disorders
Abdominal pain	1/210 (0.5%)	1
Gastritis	1/210 (0.5%)	1
Small intestinal obstruction	1/210 (0.5%)	1
General disorders
Fatigue	1/210 (0.5%)	1
Pyrexia	1/210 (0.5%)	1
Hepatobiliary disorders
Drug-induced liver injury	1/210 (0.5%)	1
Infections and infestations
Gastroenteritis	1/210 (0.5%)	1
Influenza	1/210 (0.5%)	1
Lung infection	1/210 (0.5%)	1
Pharyngeal abscess	1/210 (0.5%)	2
Pneumonia	4/210 (1.9%)	5
Sepsis	1/210 (0.5%)	1
Upper respiratory tract infection	1/210 (0.5%)	1
Urinary tract infection	1/210 (0.5%)	1
Injury, poisoning and procedural complications
Radiation necrosis	1/210 (0.5%)	1
Metabolism and nutrition disorders
Dehydration	1/210 (0.5%)	1
Failure to thrive	1/210 (0.5%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	1/210 (0.5%)	1
Nervous system disorders
Cerebral haemorrhage	1/210 (0.5%)	1
Cerebral infarction	2/210 (1%)	2
Headache	1/210 (0.5%)	1
Transient ischaemic attack	1/210 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/210 (0.5%)	1
Interstitial lung disease	2/210 (1%)	2
Pleurisy	1/210 (0.5%)	1
Pneumonia aspiration	1/210 (0.5%)	1
Pneumonitis	1/210 (0.5%)	1
Pulmonary embolism	8/210 (3.8%)	9
Vascular disorders
Deep vein thrombosis	2/210 (1%)	2
Other (Not Including Serious) Adverse Events
	AZD9291 80mg
	Affected / at Risk (%)	# Events
Total	193/210 (91.9%)
Blood and lymphatic system disorders
Anaemia	19/210 (9%)	19
Thrombocytopenia	11/210 (5.2%)	15
Eye disorders
Dry eye	11/210 (5.2%)	11
Gastrointestinal disorders
Abdominal pain upper	11/210 (5.2%)	14
Constipation	32/210 (15.2%)	38
Diarrhoea	81/210 (38.6%)	115
Nausea	34/210 (16.2%)	35
Stomatitis	22/210 (10.5%)	31
Vomiting	16/210 (7.6%)	18
General disorders
Asthenia	11/210 (5.2%)	12
Fatigue	31/210 (14.8%)	33
Oedema peripheral	17/210 (8.1%)	18
Infections and infestations
Nasopharyngitis	21/210 (10%)	23
Paronychia	32/210 (15.2%)	32
Upper respiratory tract infection	11/210 (5.2%)	11
Urinary tract infection	13/210 (6.2%)	16
Investigations
Alanine aminotransferase increased	15/210 (7.1%)	17
Aspartate aminotransferase increased	12/210 (5.7%)	12
Electrocardiogram QT prolonged	11/210 (5.2%)	13
Neutrophil count decreased	14/210 (6.7%)	17
Platelet count decreased	20/210 (9.5%)	23
White blood cell count decreased	16/210 (7.6%)	22
Metabolism and nutrition disorders
Decreased appetite	29/210 (13.8%)	32
Musculoskeletal and connective tissue disorders
Arthralgia	18/210 (8.6%)	19
Back pain	25/210 (11.9%)	26
Muscle spasms	11/210 (5.2%)	11
Musculoskeletal pain	14/210 (6.7%)	15
Pain in extremity	14/210 (6.7%)	14
Nervous system disorders
Dizziness	11/210 (5.2%)	11
Headache	20/210 (9.5%)	25
Psychiatric disorders
Insomnia	11/210 (5.2%)	11
Respiratory, thoracic and mediastinal disorders
Cough	25/210 (11.9%)	31
Dyspnoea	14/210 (6.7%)	16
Skin and subcutaneous tissue disorders
Dermatitis acneiform	16/210 (7.6%)	16
Dry skin	52/210 (24.8%)	58
Pruritus	32/210 (15.2%)	33
Rash	49/210 (23.3%)	58
Rash maculo-papular	14/210 (6.7%)	17
Skin fissures	12/210 (5.7%)	18

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review, should the submission for publication be delayed in order to file patent application. The sponsor cannot require changes to the communication and cannot extend the embargo.