A late stage clinical trial to investigate the efficacy and safety of AZD9291 versus Gefitinib or Erlotinib in patients with locally advanced or metastatic Non-Small Cell Lung Cancer

• Register: EUCTR
• Last refreshed on: 10 August 2020
• Main ID: EUCTR2014-002694-11-HU
• Date of registration: 18/10/2014
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca AB
• Public title: A late stage clinical trial to investigate the efficacy and safety of AZD9291 versus Gefitinib or Erlotinib in patients with locally advanced or metastatic Non-Small Cell Lung Cancer
• Scientific title: A phase III, double-blind, randomised study to assess the efficacy and safety 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 - FLAURA
• Date of first enrolment: 17/12/2014
• Target sample size: 530
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-002694-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: yes; Other trial design description: AZD9291 versus a standard of care Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: yes; Other specify the comparator: Gefitinib or Erlotinib; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Brazil, Bulgaria, Canada, China, Czech Republic, 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, United States, Vietnam

Contacts

• Name: Information Center
• Affiliation: AstraZeneca

• Name: Information Center
• Affiliation: AstraZeneca

Key inclusion & exclusion 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.
9. 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 =10 mm in the longest diameter (except lymph nodes which
must have a short axis of =15 mm) with computerized tomography (CT)
or magnetic resonance imaging (MRI), and which is suitable for accurate
repeated measurements.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 350
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 180

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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Locally advanced or metastatic non-small cell lung cancer, not amenable to curative surgery or radiotherapy
MedDRA version: 20.0 Level: PT Classification code 10029521 Term: Non-small cell lung cancer stage IIIB System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: LLT Classification code 10025055 Term: Lung cancer non-small cell stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Trade Name: Tagrisso (osimertinib)
Product Name: AZD9291 40 mg film-coated tablet
Product Code: AZD9291
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Osimertinib
CAS Number: 1421373-66-1
Current Sponsor code: AZD9291 mesylate
Other descriptive name: OSIMERTINIB MESYLATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Tagrisso (osimertinib)
Product Name: AZD9291 80 mg film-coated tablet
Product Code: AZD9291
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Osimertinib
CAS Number: 1421373-66-1
Current Sponsor code: AZD9291 mesylate
Other descriptive name: OSIMERTINIB MESYLATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 80-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Iressa 250 mg film-coated tablet
Product Name: Iressa 250 mg film-coated tablet
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Gefitinib
CAS Number: 184475-35-2
Other descriptive name: GEFITINIB
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 250-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Tarceva 100 mg film-coated tablet
Product Name: Tarceva 100 mg film-coated tablet
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ERLOTINIB HYDROCHLORIDE
CAS Number: 183319-69-9
Current Sponsor code: Erlotinib hydrochloride
Other descriptive name: ERLOTINIB HYDROCHLORIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Fi

Primary Outcome(s)

Primary end point(s): Progression Free Survival (PFS) using investigator assessments according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1)

Secondary Objective: 1) To assess the efficacy of AZD9291 compared with SoC EGFR-TKI therapy by assessment of PFS in patients with:
- EGFR Ex19del or L858R mutation.
- EGFRm+ (Ex19del or L858R) detectable in plasma-derived circulating tumour deoxyribonucleic acid (ctDNA).
2) To further assess the efficacy of AZD9291 compared with SoC EGFR-TKI therapy by ORR, DoR, DCR, Depth of response and Overall survival (OS)
3) To characterise the pharmacokinetics (PK) of AZD9291 and its metabolites (AZ5104 and AZ7550).
4) To assess the impact of AZD9291 compared to SoC EGFR-TKI therapy on patients’ disease-related symptoms and Health Related Quality of Life (HRQoL).
5) To assess patient satisfaction with treatment when receiving AZD9291 compared with SoC EGFR-TKI therapy.
6) To assess the safety and tolerability profile of AZD9291 compared with SoC EGFR-TKI therapy.

Timepoint(s) of evaluation of this end point: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression

Main Objective: To assess the efficacy of single agent AZD9291 compared with standard of care (SoC) Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) therapy as measured by progression free survival (PFS)

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Throughout the trial

Secondary end point(s): 1) Analysis of OS (Overall Survival) (key secondary endpoint)
2) European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 items (EORTC QLQ-C30) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Lung Cancer 13 items (EORTC QLQ-LC13).
EORTC QLQ-C30:
Questionnaire consisting of 30 items measuring subjects general cancer symptoms and functioning.
EORTC QLQ-LC13:
A complementary questionnaire measuring lung cancer symptoms and side effects from conventional chemo- and radiotherapy.
3) ORR (Objective Response Rate), Duration of Response (DoR), Disease Control Rate (DCR), Depth of response using investigator assessments according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1).
4) PK exposure parameters derived from plasma concentrations of AZD9291 and metabolites AZ5104 and AZ7550
Pharmacokinetics data from this study will be analysed using a population PK approach and may also form part of a pooled analysis with other AZD9291 studies; results from these analyses will be reported separately from the CSR
5) Safety and tolerability endpoints assessed by number and severity of adverse events, clinical chemistry, haematology, urinalysis, vital signs, physical examination, body weight, digital electrocardiogram (ECG), left Ventricular Ejection Fraction (LVEF), World Health Organization (WHO) Performance Status and Ophthalmologic assessment

Secondary ID(s)

D5160C00007

Source(s) of Monetary Support

AstraZeneca AB

Ethics review

Status: Approved
Approval date: 26/11/2014
Contact: