Clinical trial NCT02296125: AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer
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.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non Small Cell Lung Cancer
Keywords: Advanced Non-Small Cell Lung Cancer; EGFRm+; AZD9291; TKI; Phase III
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2014-11-20
Enrollment: 674
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Median Progression Free Survival (PFS) (Months)
timeFrame: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression
measure: Percentage of Participants in Progression Free Survival at 6, 12, and 18 Months
timeFrame: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression
measure: Duration of Response (DoR)
timeFrame: At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression
measure: Disease Control Rate (DCR)
timeFrame: At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression
measure: Depth of Response
timeFrame: At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression
measure: Overall Survival (OS)- Number of Participants With an Event
timeFrame: From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 29 months)
measure: Plasma Concentrations of AZD9291
timeFrame: 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)
measure: Plasma Concentrations of Metabolites AZ5104
timeFrame: 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)
measure: Plasma Concentrations of Metabolite AZ7550
timeFrame: 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)
measure: Participants Reported Outcome by Cancer Therapy Satisfaction Questionnaire 16 Items (CTSQ-16 Questionnaire)
timeFrame: Questionnaire completed in cycle 2 and 3, prior to Week 6 scan (approximately 2 months)
measure: Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ) Questionnaires Lung Cancer 13 (QLQ-LC13)
timeFrame: Questionnaires completed at baseline, first 9 months, and at week 1, 2, 3, 4, 5, 6, 12, 18, 24, 30 and 36
measure: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30)
timeFrame: Questionnaires completed at baseline, first 9 months, and at week 6, 12, 18, 24, 30, and 36.
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: Research Site
state: California
city: Santa Rosa
country: United States
facility: Research Site
state: California
city: West Hills
country: United States
facility: Research Site
state: California
city: Tampa
country: United States
facility: Research Site
state: Florida
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Marietta
country: United States
facility: Research Site
state: Georgia
city: Louisville
country: United States
facility: Research Site
state: Kentucky
city: Bethesda
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Minneapolis
country: United States
facility: Research Site
state: Minnesota
city: Lebanon
country: United States
facility: Research Site
state: New Hampshire
city: Salisbury
country: United States
facility: Research Site
state: North Carolina
city: Burlington
country: United States
facility: Research Site
state: Vermont
city: Camperdown
country: Australia
facility: Research Site
city: Chermside
country: Australia
facility: Research Site
city: Clayton
country: Australia
facility: Research Site
city: Heidelberg
country: Australia
facility: Research Site
city: Kogarah
country: Australia
facility: Research Site
city: Nedlands
country: Australia
facility: Research Site
city: Woolloongabba
country: Australia
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Liège
country: Belgium
facility: Research Site
city: Roeselare
country: Belgium
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: Hamilton
country: Canada
facility: Research Site
state: Ontario
city: Ottawa
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Beijing
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Changchun
country: China
facility: Research Site
city: Changchun
country: China
facility: Research Site
city: Chongqing
country: China
facility: Research Site
city: Chongqing
country: China
facility: Research Site
city: Chongqing
country: China
facility: Research Site
city: Fuzhou
country: China
facility: Research Site
city: Guangzhou
country: China
facility: Research Site
city: Hangzhou
country: China
facility: Research Site
city: Nanjing
country: China
facility: Research Site
city: Nanning
country: China
facility: Research Site
city: Shanghai
country: China
facility: Research Site
city: Shenyang
country: China
facility: Research Site
city: Suzhou
country: China
facility: Research Site
city: Wuhan
country: China
facility: Research Site
city: Xi'an
country: China
facility: Research Site
city: Xi'an
country: China
facility: Research Site
city: Yangzhou
country: China
facility: Research Site
city: Ürümqi
country: China
facility: Research Site
city: Ostrava
country: Czechia
facility: Research Site
city: Caen
country: France
facility: Research Site
city: Creteil
country: France
facility: Research Site
city: Lyon Cedex 08
country: France
facility: Research Site
city: Nantes
country: France
facility: Research Site
city: Toulon Naval
country: France
facility: Research Site
city: Villejuif
country: France
facility: Research Site
city: Bad Berka
country: Germany
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Gauting
country: Germany
facility: Research Site
city: Halle
country: Germany
facility: Research Site
city: Heidelberg
country: Germany
facility: Research Site
city: Karlsruhe
country: Germany
facility: Research Site
city: Lübeck
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Villingen-Schwenningen
country: Germany
facility: Research Site
city: Farkasgyepü
country: Hungary
facility: Research Site
city: Gyöngyös - Mátraháza
country: Hungary
facility: Research Site
city: Miskolc
country: Hungary
facility: Research Site
city: Székesfehérvár
country: Hungary
facility: Research Site
city: Tatabánya
country: Hungary
facility: Research Site
city: Zalaegerszeg
country: Hungary
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Kfar-Saba
country: Israel
facility: Research Site
city: Petach Tikva
country: Israel
facility: Research Site
city: Tel Hashomer
country: Israel
facility: Research Site
city: Cremona
country: Italy
facility: Research Site
city: Lecce
country: Italy
facility: Research Site
city: Lecco
country: Italy
facility: Research Site
city: Orbassano
country: Italy
facility: Research Site
city: Parma
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Sondrio
country: Italy
facility: Research Site
city: Terni
country: Italy
facility: Research Site
city: Chuo-ku
country: Japan
facility: Research Site
city: Fukuoka-shi
country: Japan
facility: Research Site
city: Hirakata-shi
country: Japan
facility: Research Site
city: Kanazawa-shi
country: Japan
facility: Research Site
city: Kashiwa
country: Japan
facility: Research Site
city: Kobe-shi
country: Japan
facility: Research Site
city: Matsuyama-shi
country: Japan
facility: Research Site
city: Natori-shi
country: Japan
facility: Research Site
city: Osaka-shi
country: Japan
facility: Research Site
city: Osakasayama-shi
country: Japan
facility: Research Site
city: Sagamihara-shi
country: Japan
facility: Research Site
city: Sakai-shi
country: Japan
facility: Research Site
city: Sendai-shi
country: Japan
facility: Research Site
city: Sunto-gun
country: Japan
facility: Research Site
city: Yokohama-shi
country: Japan
facility: Research Site
city: Yokohama-shi
country: Japan
facility: Research Site
city: Yokohama-shi
country: Japan
facility: Research Site
city: Yokohama-shi
country: Japan
facility: Research Site
city: Cheongju-si
country: Korea, Republic of
facility: Research Site
city: Incheon
country: Korea, Republic of
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Kuala Lumpur
country: Malaysia
facility: Research Site
city: Kuantan
country: Malaysia
facility: Research Site
city: Kuching
country: Malaysia
facility: Research Site
city: Cebu
country: Philippines
facility: Research Site
city: Manila
country: Philippines
facility: Research Site
city: Quezon City
country: Philippines
facility: Research Site
city: Brzozoów
country: Poland
facility: Research Site
city: Otwock
country: Poland
facility: Research Site
city: Poznań
country: Poland
facility: Research Site
city: Szczecin
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Amadora
country: Portugal
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Porto
country: Portugal
facility: Research Site
city: Vila Nova de Gaia
country: Portugal
facility: Research Site
city: Bucharest
country: Romania
facility: Research Site
city: Bucuresti
country: Romania
facility: Research Site
city: Craiova
country: Romania
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Coruña
country: Spain
facility: Research Site
city: Lugo
country: Spain
facility: Research Site
city: Lérida
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Málaga
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Zaragoza
country: Spain
facility: Research Site
city: Linköping
country: Sweden
facility: Research Site
city: Luzern
country: Switzerland
facility: Research Site
city: Winterthur
country: Switzerland
facility: Research Site
city: Zürich
country: Switzerland
facility: Research Site
city: Kaohsiung
country: Taiwan
facility: Research Site
city: Taichung City
country: Taiwan
facility: Research Site
city: Tainan City
country: Taiwan
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Taoyuan City
country: Taiwan
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Bangkok
country: Thailand
facility: Research Site
city: Hat Yai
country: Thailand
facility: Research Site
city: Muang
country: Thailand
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: Izmir
country: Turkey
facility: Research Site
city: Dnipro
country: Ukraine
facility: Research Site
city: Kryvyi Rih
country: Ukraine
facility: Research Site
city: Lviv
country: Ukraine
facility: Research Site
city: Sumy
country: Ukraine
facility: Research Site
city: Edinburgh
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Maidstone
country: United Kingdom
facility: Research Site
city: Withington
country: United Kingdom
facility: Research Site
city: Hanoi
country: Vietnam
facility: Research Site
city: Hanoi
country: Vietnam
facility: Research Site
city: Ho Chi Minh City
country: Vietnam
facility: Research Site
Study officials:
References:
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citation: Leighl NB, Karaseva N, Nakagawa K, Cho BC, Gray JE, Hovey T, Walding A, Ryden A, Novello S. Patient-reported outcomes from FLAURA: Osimertinib versus erlotinib or gefitinib in patients with EGFR-mutated advanced non-small-cell lung cancer. Eur J Cancer. 2020 Jan;125:49-57. doi: 10.1016/j.ejca.2019.11.006. Epub 2019 Dec 12.
citation: Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, Shah R, Cobo M, Lee KH, Cheema P, Tiseo M, John T, Lin MC, Imamura F, Kurata T, Todd A, Hodge R, Saggese M, Rukazenkov Y, Soria JC; FLAURA Investigators. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020 Jan 2;382(1):41-50. doi: 10.1056/NEJMoa1913662. Epub 2019 Nov 21.
citation: Brown H, Vansteenkiste J, Nakagawa K, Cobo M, John T, Barker C, Kohlmann A, Todd A, Saggese M, Chmielecki J, Markovets A, Scott M, Ramalingam SS. Programmed Cell Death Ligand 1 Expression in Untreated EGFR Mutated Advanced NSCLC and Response to Osimertinib Versus Comparator in FLAURA. J Thorac Oncol. 2020 Jan;15(1):138-143. doi: 10.1016/j.jtho.2019.09.009. Epub 2019 Oct 9.
citation: Gray JE, Okamoto I, Sriuranpong V, Vansteenkiste J, Imamura F, Lee JS, Pang YK, Cobo M, Kasahara K, Cheng Y, Nogami N, Cho EK, Su WC, Zhang G, Huang X, Li-Sucholeiki X, Lentrichia B, Dearden S, Jenkins S, Saggese M, Rukazenkov Y, Ramalingam SS. Tissue and Plasma EGFR Mutation Analysis in the FLAURA Trial: Osimertinib versus Comparator EGFR Tyrosine Kinase Inhibitor as First-Line Treatment in Patients with EGFR-Mutated Advanced Non-Small Cell Lung Cancer. Clin Cancer Res. 2019 Nov 15;25(22):6644-6652. doi: 10.1158/1078-0432.CCR-19-1126. Epub 2019 Aug 22.
citation: Planchard D, Boyer MJ, Lee JS, Dechaphunkul A, Cheema PK, Takahashi T, Gray JE, Tiseo M, Ramalingam SS, Todd A, McKeown A, Rukazenkov Y, Ohe Y. Postprogression Outcomes for Osimertinib versus Standard-of-Care EGFR-TKI in Patients with Previously Untreated EGFR-mutated Advanced Non-Small Cell Lung Cancer. Clin Cancer Res. 2019 Apr 1;25(7):2058-2063. doi: 10.1158/1078-0432.CCR-18-3325. Epub 2019 Jan 18.
citation: Ohe Y, Imamura F, Nogami N, Okamoto I, Kurata T, Kato T, Sugawara S, Ramalingam SS, Uchida H, Hodge R, Vowler SL, Walding A, Nakagawa K. Osimertinib versus standard-of-care EGFR-TKI as first-line treatment for EGFRm advanced NSCLC: FLAURA Japanese subset. Jpn J Clin Oncol. 2019 Jan 1;49(1):29-36. doi: 10.1093/jjco/hyy179.
citation: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. doi: 10.1056/NEJMoa1713137. Epub 2017 Nov 18.