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NCT02296125 Clinical Trial

AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer

Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non Small Cell Lung Cancer Clinical Trial

— FLAURA  

Official title:
A Phase III, Double-blind, Randomised Study to Assess the Safety and Efficacy of AZD9291 Versus a Standard of Care Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor as First Line Treatment in Patients With Epidermal Growth Factor Receptor Mutation Positive, Locally Advanced or Metastatic Non Small Cell Lung Cancer.

Clinical Trial Details — Status: Active, not recruiting

Administrative data
NCT number NCT02296125
Other study ID # D5160C00007
Secondary ID U1111-1160-22422
Status Active, not recruiting
Phase Phase 3
First received
Last updated
Start date December 3, 2014
Est. completion date January 31, 2025

Study information
Verified date May 2024
Source AstraZeneca
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

To assess the efficacy and safety of AZD9291 versus a standard of care epidermal growth factor receptor tyrosine kinase inhibitor in patients with locally advanced or Metastatic Non Small Cell Lung Cancer

Description:

This is a Phase III, double-blind, randomised study assessing the efficacy and safety of AZD9291 (80 mg orally, once daily) versus a standard of care (SoC) Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) (either gefitinib [250 mg orally, once daily] or erlotinib [150 mg orally, once daily]) in patients with locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) that is known to be EGFR sensitising mutation (EGFRm) positive, treatment-naïve and eligible for first-line treatment with an EGFR-TKI.

Recruitment information / eligibility
Status Active, not recruiting
Enrollment 674
Est. completion date January 31, 2025
Est. primary completion date June 19, 2017
Accepts healthy volunteers No
Gender All
Age group 18 Years to 100 Years
Eligibility Inclusion Criteria: 1. Male or female, aged at least 18 years. 2. Pathologically confirmed adenocarcinoma of the lung. 3. Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy. 4. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R). 5. Mandatory provision of an unstained, archived tumour tissue sample in a quantity sufficient to allow for central analysis of EGFR mutation status. 6. Patients must be treatment-naïve for locally advanced or metastatic NSCLC and eligible to receive first-line treatment with gefitinib or erlotinib as selected by the participating centre. Prior adjuvant and neo-adjuvant therapy is permitted(chemotherapy, radiotherapy, investigational agents). 7. Provision of informed consent prior to any study specific procedures, sampling, and analysis. 8. World Health Organization Performance Status of 0 to 1 with no clinically significant deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks Exclusion Criteria: 1. Treatment with any of the following: - Prior treatment with any systemic anti-cancer therapy for locally advanced/metastatic NSCLC. - Prior treatment with an EGFR-TKI. - Major surgery within 4 weeks of the first dose of study drug. - Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug. - Patients currently receiving medications or herbal supplements known to be potent inducers of cytochrome P450 (CYP) 3A4. - Alternative anti-cancer treatment - Treatment with an investigational drug within five half-lives of the compound or any of its related material. 2. Any concurrent and/or other active malignancy that has required treatment within 2 years of first dose of study drug. 3. Spinal cord compression, symptomatic and unstable brain metastases, except for those patients who have completed definitive therapy, are not on steroids, have a stable neurologic status for at least 2 weeks after completion of the definitive therapy and steroids. 4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). 5. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD9291. 6. Any of the following cardiac criteria: - Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTcF value. - Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG. - Any patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval. 7. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. 8. Involvement in the planning and/or conduct of the study

Study Design

Related Conditions & MeSH terms

Intervention

Drug:
• AZD9291 80 mg/40 mg + placebo
The initial dose of AZD9291 80 mg once daily can be reduced to 40 mg once daily under specific circumstances. A cycle of treatment is defined as 21 days of once daily treatment. Number of Cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.
• Placebo Erlotinib 150/100mg
The initial dose of Placebo Erlotinib 150 mg once daily can be reduced to Placebo 100 mg once daily under specific circumstances. A cycle of treatment is defined as 21 days of once daily treatment. Number of cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.
• Placebo Gefitinib 250 mg
The initial dose of Placebo Gefitinib 250 mg once daily cannot be reduced. A cycle of treatment is defined as 21 days of once daily treatment. Number of cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.
• Erlotinib 150/100 mg
The initial dose of Erlotinib 150mg once daily can be reduced to 10 mg once daily under specific circumstances. A cycle of treatment is defined as 21 days of once daily treatment. Number of Cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria. Following objective disease progression according to RECIST 1.1, as per investigator assessment, patients who were randomized to Standard of Care arm may have the option to receive open-label AZD9291 (crossover to active AZD9291).
• Gefitinib 250 mg
The initial dose of Gefitinib 250mg once daily cannot be reduced. A cycle of treatment is defined as 21 days of once daily treatment. Number of Cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria. Following objective disease progression according to RECIST 1.1, as per investigator assessment, patients who were randomized to Standard of Care arm may have the option to receive open-label AZD9291 (crossover to active AZD9291).
• Placebo AZD9291 80 mg/ 40 mg
The initial dose of Placebo AZD9291 80 mg once daily can be reduced to Placebo AZD9291 40 mg once daily under specific circumstances. A cycle of treatment is defined as 21 days of once daily treatment. Number of cycles: as long as patients are continuing to show clinical benefit, as judged by the Investigator, and in the absence of discontinuation criteria.

Locations
Country Name City State
Australia Research Site Camperdown
Australia Research Site Chermside
Australia Research Site Clayton
Australia Research Site Heidelberg
Australia Research Site Kogarah
Australia Research Site Nedlands
Australia Research Site Woolloongabba
Belgium Research Site Leuven
Belgium Research Site Liège
Belgium Research Site Roeselare
Brazil Research Site Porto Alegre
Bulgaria Research Site Sofia
Canada Research Site Edmonton Alberta
Canada Research Site Hamilton Ontario
Canada Research Site Ottawa Ontario
Canada Research Site Toronto Ontario
Canada Research Site Toronto Ontario
Canada Research Site Toronto Ontario
China Research Site Beijing
China Research Site Beijing
China Research Site Changchun
China Research Site Changchun
China Research Site Chongqing
China Research Site Chongqing
China Research Site Chongqing
China Research Site Fuzhou
China Research Site Guangzhou
China Research Site Hangzhou
China Research Site Nanjing
China Research Site Nanning
China Research Site Shanghai
China Research Site Shenyang
China Research Site Suzhou
China Research Site Ürümqi
China Research Site Wuhan
China Research Site Xi'an
China Research Site Xi'an
China Research Site Yangzhou
Czechia Research Site Ostrava
France Research Site Caen
France Research Site Creteil
France Research Site Lyon Cedex 08
France Research Site Nantes
France Research Site Toulon Naval
France Research Site Villejuif
Germany Research Site Bad Berka
Germany Research Site Berlin
Germany Research Site Gauting
Germany Research Site Halle
Germany Research Site Heidelberg
Germany Research Site Karlsruhe
Germany Research Site Lübeck
Germany Research Site München
Germany Research Site Villingen-Schwenningen
Hungary Research Site Farkasgyepü
Hungary Research Site Gyöngyös - Mátraháza
Hungary Research Site Miskolc
Hungary Research Site Székesfehérvár
Hungary Research Site Tatabánya
Hungary Research Site Zalaegerszeg
Israel Research Site Haifa
Israel Research Site Kfar-Saba
Israel Research Site Petach Tikva
Israel Research Site Tel Hashomer
Italy Research Site Cremona
Italy Research Site Lecce
Italy Research Site Lecco
Italy Research Site Orbassano
Italy Research Site Parma
Italy Research Site Roma
Italy Research Site Sondrio
Italy Research Site Terni
Japan Research Site Chuo-ku
Japan Research Site Fukuoka-shi
Japan Research Site Hirakata-shi
Japan Research Site Kanazawa-shi
Japan Research Site Kashiwa
Japan Research Site Kobe-shi
Japan Research Site Matsuyama-shi
Japan Research Site Natori-shi
Japan Research Site Osaka-shi
Japan Research Site Osakasayama-shi
Japan Research Site Sagamihara-shi
Japan Research Site Sakai-shi
Japan Research Site Sendai-shi
Japan Research Site Sunto-gun
Japan Research Site Yokohama-shi
Japan Research Site Yokohama-shi
Japan Research Site Yokohama-shi
Japan Research Site Yokohama-shi
Korea, Republic of Research Site Cheongju-si
Korea, Republic of Research Site Incheon
Korea, Republic of Research Site Seongnam-si
Korea, Republic of Research Site Seoul
Korea, Republic of Research Site Seoul
Korea, Republic of Research Site Seoul
Korea, Republic of Research Site Seoul
Malaysia Research Site Kuala Lumpur
Malaysia Research Site Kuantan
Malaysia Research Site Kuching
Philippines Research Site Cebu
Philippines Research Site Manila
Philippines Research Site Quezon City
Poland Research Site Brzozoów
Poland Research Site Otwock
Poland Research Site Poznan
Poland Research Site Szczecin
Poland Research Site Warszawa
Portugal Research Site Amadora
Portugal Research Site Lisboa
Portugal Research Site Porto
Portugal Research Site Vila Nova de Gaia
Romania Research Site Bucharest
Romania Research Site Bucuresti
Romania Research Site Craiova
Russian Federation Research Site Saint Petersburg
Russian Federation Research Site Saint Petersburg
Russian Federation Research Site Saint Petersburg
Spain Research Site Barcelona
Spain Research Site Barcelona
Spain Research Site Barcelona
Spain Research Site Coruña
Spain Research Site Lérida
Spain Research Site Lugo
Spain Research Site Madrid
Spain Research Site Málaga
Spain Research Site Sevilla
Spain Research Site Zaragoza
Sweden Research Site Linköping
Switzerland Research Site Luzern
Switzerland Research Site Winterthur
Switzerland Research Site Zürich
Taiwan Research Site Kaohsiung
Taiwan Research Site Taichung City
Taiwan Research Site Tainan
Taiwan Research Site Tainan City
Taiwan Research Site Taoyuan City
Thailand Research Site Bangkok
Thailand Research Site Bangkok
Thailand Research Site Bangkok
Thailand Research Site Hat Yai
Thailand Research Site Muang
Turkey Research Site Ankara
Turkey Research Site Istanbul
Turkey Research Site Izmir
Ukraine Research Site Dnipro
Ukraine Research Site Kryvyi Rih
Ukraine Research Site Lviv
Ukraine Research Site Sumy
United Kingdom Research Site London
United Kingdom Research Site Maidstone
United Kingdom Research Site Withington
United States Research Site Anaheim California
United States Research Site Atlanta Georgia
United States Research Site Atlanta Georgia
United States Research Site Bethesda Maryland
United States Research Site Boston Massachusetts
United States Research Site Burlington Vermont
United States Research Site Lebanon New Hampshire
United States Research Site Louisville Kentucky
United States Research Site Marietta Georgia
United States Research Site Minneapolis Minnesota
United States Research Site Salisbury North Carolina
United States Research Site Santa Rosa California
United States Research Site Tampa Florida
United States Research Site West Hills California
Vietnam Research Site Hanoi
Vietnam Research Site Hanoi
Vietnam Research Site Ho Chi Minh City

Sponsors (2)
Lead Sponsor Collaborator
AstraZeneca Parexel

Countries where clinical trial is conducted

United States,  Vietnam,  Australia,  Belgium,  Brazil,  Bulgaria,  Canada,  China,  Czechia,  France,  Germany,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Malaysia,  Philippines,  Poland,  Portugal,  Romania,  Russian Federation,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand,  Turkey,  Ukraine,  United Kingdom, 

Outcome
Type Measure Description Time frame Safety issue
Primary Median Progression Free Survival (PFS) (Months) Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent osimertinib compared with SoC EGFR-TKI therapy as measured by PFS. The primary endpoint of PFS was based on Investigator assessment. At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression
Primary Percentage of Participants in Progression Free Survival at 6, 12, and 18 Months Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent osimertinib compared with SoC EGFR-TKI therapy as measured by PFS. At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression
Secondary Objective Response Rate (ORR) ORR was defined as the number (%) of participants with measurable disease with at least 1 visit response of Complete response (CR) or Partial response (PR) and it was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy. ORR was based on Investigator assessment. At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression
Secondary Duration of Response (DoR) Duration of response was defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy. At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression
Secondary Disease Control Rate (DCR) The DCR was defined as the percentage of participants who had a best overall response (BOR) of Complete response (CR), Partial response (PR) or Stable disease (SD) =6 weeks prior to any Progressive disease (PD) event and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy. At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression
Secondary Depth of Response The Depth of response was defined as the relative change in the sum of the longest diameters of Response Evaluation Criteria in Solid Tumors (RECIST) Target lesions (TLs) at the nadir, in the absence of new lesions (NLs) or progression of Non-target lesions (NTLs), compared to baseline and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression
Secondary Overall Survival (OS)- Number of Participants With an Event Overall survival was defined as the time from the date of randomisation until death from any cause and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 29 months)
Secondary Plasma Concentrations of AZD9291 To characterise the pharmacokinetics (PK) of osimertinib Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months)
Secondary Plasma Concentrations of Metabolites AZ5104 To characterise the pharmacokinetics (PK) of osimertinib metabolite AZ5104. Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months)
Secondary Plasma Concentrations of Metabolite AZ7550 To characterise the pharmacokinetics (PK) of osimertinib metabolite AZ7550. Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months)
Secondary Participants Reported Outcome by Cancer Therapy Satisfaction Questionnaire 16 Items (CTSQ-16 Questionnaire) The CTSQ-16 was a 16-item questionnaire measuring 3 domains related to participant's satisfaction with cancer therapy: Expectations of therapy, Feelings about side effects, and Satisfaction with therapy. Scores ranged from 0 to 100 for each domain, with a higher score associated with the best outcome on each domain. The three domains of interest were separately analysed using an ANCOVA stratified by race (Asian versus Non-Asian) and mutation type (Ex19del versus L858R). The results of the analyses were presented in terms of mean together with standard deviation. Questionnaire completed in cycle 2 and 3, prior to Week 6 scan (approximately 2 months)
Secondary Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ) Questionnaires Lung Cancer 13 (QLQ-LC13) The EORTC QLQ-LC13 was a lung-cancer-specific module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, dyspnoea, and site-specific pain); treatment related side-effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia); and pain medication. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items. Higher scores on the global health status/QoL and functioning scales indicated better health status/QoL and function. Higher scores on the symptoms scales indicated greater symptom burden. The analysis was performed using a Mixed-effects model for repeated measures analysis on the change from baseline in PRO symptom score at each visit up to 9 months (281 days), including participants, treatment, visit and treatment by visit interaction as explanatory variables, the baseline PRO score as a covariate along with the baseline PRO score by visit interaction, using an unstructured covariance structure. Questionnaires completed at baseline, first 9 months, and at week 1, 2, 3, 4, 5, 6, 12, 18, 24, 30 and 36
Secondary Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30) The EORTC QLQ-C30 cancer-specific questionnaire consisted of 30 questions, combined to produce 5 functional scales, 3 symptom scales, 6 individual items, and a global measure of health status/QoL. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, the functional scales, and the global health status/QoL scale in the EORTC QLQ-C30. Higher scores on the global health status and functioning scales indicated better health status/function. Higher scores on the symptoms scales indicated greater symptom burden. The analysis was performed using a Mixed-effects model for repeated measures analysis on the change from baseline in PRO symptom score at each visit up to 9 months (281 days), including participants, treatment, visit and treatment by visit interaction as explanatory variables, the baseline PRO score as a covariate along with the baseline PRO score by visit interaction, using an unstructured covariance structure. Questionnaires completed at baseline, first 9 months, and at week 6, 12, 18, 24, 30, and 36.

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