AZD9291 First Time In Patients Ascending Dose Study (AURA)

• ClinicalTrials.gov Identifier: NCT01802632
• Recruitment Status: Completed
• First Posted: March 1, 2013
• Results First Posted: October 6, 2016
• Last Update Posted: January 18, 2024
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

This study will treat patients with advanced NSCLC who have already received at least one course of specific anti-cancer treatment but the tumour has started to re-grow following that treatment. This is the first time this drug has ever been tested in patients, and so it will help to understand what type of side effects may occur with the drug treatment, it will measure the levels of drug in the body, it will also measure the anti-cancer activity. By using these pieces of information together the best dose of this drug to use in further clinical trials will be selected.

Condition or disease	Intervention/treatment	Phase
Advanced Non Small Cell Lung Cancer; Advanced (Inoperable) Non Small Cell Lung Cancer	Drug: AZD9291	Phase 1; Phase 2

Detailed Description:

A Phase I/II, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of Ascending Doses of AZD9291 in Patients with Advanced Non Small Cell Lung Cancer who have Progressed Following Prior Therapy with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent (AURA)

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 603 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AZD9291 in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent
• Actual Study Start Date: March 4, 2013
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: December 13, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Daily dose of AZD9291; Daily oral dose of AZD9291	Drug: AZD9291; Starting dose 20 mg, administered once daily. If tolerated subsequent cohorts will test increasing doses of AZD9291, until a maximum tolerated dose or maximum feasible dose is defined

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate (ORR) for Dose Expansion Population [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at 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 (by investigator assessment) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.
2. Best Objective Response (BOR) for Dose Escalation Population [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 25 months (at 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. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.
3. Objective Response Rate (ORR) for Extension Population [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 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 (by independent central 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) for Dose Expansion Population [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at 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. Progression-Free Survival (PFS) for Dose Expansion Population [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at 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 central 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.
3. Best Objective Response (BOR) for 80mg AZD9291 Extension Population [ Time Frame: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 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. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 130 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses
• Aged at least 18 years. Patients from Japan aged at least 20 years.
• Histological or cytological confirmation diagnosis of Non Small Cell Lung Cancer (NSCLC).
• Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI e.g. gefitinib or erlotinib (with the exception of 1st line expansion cohort). 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.

• Patients (with the exception of 1st line expansion cohort) must fulfil one of the following:

  • Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR
  • Must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (Jackman et al 2010) followed by systemic objective progression (RECIST or WHO) while on continuous treatment with EGFR TKI.
• Previous treatment with a single-agent EGFR TKI (e.g. gefitinib or erlotinib).
• Females should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test prior to start of dosing or evidence of non-child bearing potential.
• Male patients should be willing to use barrier contraception.
• For 1st Line expansion cohort ONLY, confirmation that the tumour is EGFRm+ve and have had no prior therapy for their advanced disease (for 1st line patients biopsy will be at time of diagnosis of advanced disease).
• For dose expansion and extension cohorts, patients must also have confirmation of tumour T790M mutation status (confirmed positive or negative) from a biopsy sample taken after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy).

Prior to entry a result from the central analysis of the patient's T790M mutation status must be obtained.

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

Exclusion Criteria:

• Treatment with an EGFR TKI (erlotinib or gefitinib) within 8 days (approximately 5x half-life) of the first dose of study treatment.
• Any cytotoxic chemotherapy, investigational agents or other anticancer drugs from the treatment of advanced NSCLC from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment.
• AZD9291 in the present study (ie, dosing with AZD9291 previously initiated in this study).
• Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection.
• Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.

Contacts and Locations

Locations

United States, Colorado

Research Site

Aurora, Colorado, United States, 80045

United States, Georgia

Research Site

Atlanta, Georgia, United States, 30322

United States, Massachusetts

Research Site

Boston, Massachusetts, United States, 02114

Research Site

Boston, Massachusetts, United States, 02215

United States, North Carolina

Research Site

Charlotte, North Carolina, United States, 28204

United States, Tennessee

Research Site

Nashville, Tennessee, United States, 37232

United States, Texas

Research Site

Houston, Texas, United States, 77030

Australia

Research Site

Heidelberg, Australia, 3084

Research Site

Kogarah, Australia, 2217

Research Site

Nedlands, Australia, 6009

France

Research Site

Pierre Benite CEDEX, France, 69310

Research Site

Saint Herblain Cedex, France, 44805

Research Site

Villejuif, France, 94800

Germany

Research Site

Essen, Germany, 45122

Research Site

Köln, Germany, 50924

Research Site

Würzburg, Germany, 97080

Italy

Research Site

Genova, Italy, 16100

Research Site

Orbassano, Italy, 10043

Research Site

Roma, Italy, 00144

Japan

Research Site

Chiba-shi, Japan, 260-8717

Research Site

Fukuoka-shi, Japan, 811-1395

Research Site

Fukuoka, Japan, 812-8582

Research Site

Habikino-shi, Japan, 583-8588

Research Site

Hirakata-shi, Japan, 573-1191

Research Site

Hiroshima-shi, Japan, 730-8518

Research Site

Kanazawa, Japan, 920-8641

Research Site

Kashiwa, Japan, 227-8577

Research Site

Kobe-shi, Japan, 650-0047

Research Site

Matsuyama-shi, Japan, 790-0007

Research Site

Okayama-shi, Japan, 700-8558

Research Site

Shinjuku-ku, Japan, 160-0023

Research Site

Sunto-gun, Japan, 411-8777

Research Site

Takatsuki-shi, Japan, 569-8686

Research Site

Yokohama-shi, Japan, 221-0855

Korea, Republic of

Research Site

Seoul, Korea, Republic of, 03080

Research Site

Seoul, Korea, Republic of, 03722

Research Site

Seoul, Korea, Republic of, 05505

Research Site

Seoul, Korea, Republic of, 6351

Spain

Research Site

Madrid, Spain, 08035

Research Site

Madrid, Spain, 28041

Research Site

Sevilla, Spain, 41013

Taiwan

Research Site

Tainan, Taiwan, 704

Research Site

Taipei, Taiwan, 10002

United Kingdom

Research Site

Manchester, United Kingdom, M20 4BX

Research Site

Newcastle upon Tyne, United Kingdom, NE7 7DN

Sponsors and Collaborators

AstraZeneca

Investigators

• Study Director: Yuri Rukazenkov; AstraZeneca

More Information

Additional Information:

D5160C00001AURA_Protocol_for_AZ_ClinTrials_Website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Martin ML, Correll J, Walding A, Ryden A. How patients being treated for non-small cell lung cancer value treatment benefit despite side effects. Qual Life Res. 2022 Jan;31(1):135-146. doi: 10.1007/s11136-021-02882-6. Epub 2021 May 31.

Ahn MJ, Han JY, Kim DW, Cho BC, Kang JH, Kim SW, Yang JC, Mitsudomi T, Lee JS. Osimertinib in Patients with T790M-Positive Advanced Non-small Cell Lung Cancer: Korean Subgroup Analysis from Phase II Studies. Cancer Res Treat. 2020 Jan;52(1):284-291. doi: 10.4143/crt.2019.200. Epub 2019 Jul 23.

Ahn MJ, Tsai CM, Shepherd FA, Bazhenova L, Sequist LV, Hida T, Yang JCH, Ramalingam SS, Mitsudomi T, Janne PA, Mann H, Cantarini M, Goss G. Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: Long-term follow-up from a pooled analysis of 2 phase 2 studies. Cancer. 2019 Mar 15;125(6):892-901. doi: 10.1002/cncr.31891. Epub 2018 Dec 4.

Oxnard GR, Hu Y, Mileham KF, Husain H, Costa DB, Tracy P, Feeney N, Sholl LM, Dahlberg SE, Redig AJ, Kwiatkowski DJ, Rabin MS, Paweletz CP, Thress KS, Janne PA. Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib. JAMA Oncol. 2018 Nov 1;4(11):1527-1534. doi: 10.1001/jamaoncol.2018.2969.

Kiura K, Yoh K, Katakami N, Nogami N, Kasahara K, Takahashi T, Okamoto I, Cantarini M, Hodge R, Uchida H. Osimertinib in patients with epidermal growth factor receptor T790M advanced non-small cell lung cancer selected using cytology samples. Cancer Sci. 2018 Apr;109(4):1177-1184. doi: 10.1111/cas.13511. Epub 2018 Feb 27.

Goss G, Tsai CM, Shepherd FA, Ahn MJ, Bazhenova L, Crino L, de Marinis F, Felip E, Morabito A, Hodge R, Cantarini M, Johnson M, Mitsudomi T, Janne PA, Yang JC. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol. 2018 Mar 1;29(3):687-693. doi: 10.1093/annonc/mdx820.

Ramalingam SS, Yang JC, Lee CK, Kurata T, Kim DW, John T, Nogami N, Ohe Y, Mann H, Rukazenkov Y, Ghiorghiu S, Stetson D, Markovets A, Barrett JC, Thress KS, Janne PA. Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2018 Mar 20;36(9):841-849. doi: 10.1200/JCO.2017.74.7576. Epub 2017 Aug 25.

Thress KS, Jacobs V, Angell HK, Yang JC, Sequist LV, Blackhall F, Su WC, Schuler M, Wolf J, Gold KA, Cantarini M, Barrett JC, Janne PA. Modulation of Biomarker Expression by Osimertinib: Results of the Paired Tumor Biopsy Cohorts of the AURA Phase I Trial. J Thorac Oncol. 2017 Oct;12(10):1588-1594. doi: 10.1016/j.jtho.2017.07.011. Epub 2017 Jul 24.

Dearden S, Brown H, Jenkins S, Thress KS, Cantarini M, Cole R, Ranson M, Janne PA. EGFR T790M mutation testing within the osimertinib AURA Phase I study. Lung Cancer. 2017 Jul;109:9-13. doi: 10.1016/j.lungcan.2017.04.011. Epub 2017 Apr 19.

Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, Pickup K, Jordan A, Hickey M, Grist M, Box M, Johnstrom P, Varnas K, Malmquist J, Thress KS, Janne PA, Cross D. Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res. 2016 Oct 15;22(20):5130-5140. doi: 10.1158/1078-0432.CCR-16-0399. Epub 2016 Jul 19.

Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M, Yang JC, Barrett JC, Janne PA. Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2016 Oct 1;34(28):3375-82. doi: 10.1200/JCO.2016.66.7162. Epub 2016 Jun 27.

Thress KS, Brant R, Carr TH, Dearden S, Jenkins S, Brown H, Hammett T, Cantarini M, Barrett JC. EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer. 2015 Dec;90(3):509-15. doi: 10.1016/j.lungcan.2015.10.004. Epub 2015 Oct 9.

Kim TM, Song A, Kim DW, Kim S, Ahn YO, Keam B, Jeon YK, Lee SH, Chung DH, Heo DS. Mechanisms of Acquired Resistance to AZD9291: A Mutation-Selective, Irreversible EGFR Inhibitor. J Thorac Oncol. 2015 Dec;10(12):1736-44. doi: 10.1097/JTO.0000000000000688.

Yu HA, Tian SK, Drilon AE, Borsu L, Riely GJ, Arcila ME, Ladanyi M. Acquired Resistance of EGFR-Mutant Lung Cancer to a T790M-Specific EGFR Inhibitor: Emergence of a Third Mutation (C797S) in the EGFR Tyrosine Kinase Domain. JAMA Oncol. 2015 Oct;1(7):982-4. doi: 10.1001/jamaoncol.2015.1066. No abstract available.

Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1689-99. doi: 10.1056/NEJMoa1411817.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01802632
• Other Study ID Numbers: D5160C00001; 2012-004628-39 ( EudraCT Number )
• First Posted: March 1, 2013
• Results First Posted: October 6, 2016
• Last Update Posted: January 18, 2024
• Last Verified: January 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

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.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

Keywords provided by AstraZeneca:

Oncology,; Non Small Cell Lung Cancer,; Metastatic,; EGFR sensitivity mutation,; T790M resistance mutation

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Osimertinib; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents