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.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 674
- 试验地点
- 171
- 主要终点
- Median Progression Free Survival (PFS) (Months)
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, aged at least 18 years.
- •Pathologically confirmed adenocarcinoma of the lung.
- •Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy.
- •The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R).
- •Mandatory provision of an unstained, archived tumour tissue sample in a quantity sufficient to allow for central analysis of EGFR mutation status.
- •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).
- •Provision of informed consent prior to any study specific procedures, sampling, and analysis.
- •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
排除标准
- •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) 3A
- •Alternative anti-cancer treatment
- •Treatment with an investigational drug within five half-lives of the compound or any of its related material.
- •Any concurrent and/or other active malignancy that has required treatment within 2 years of first dose of study drug.
- •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.
- •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).
- •Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD
- •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.
- •Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
- •Involvement in the planning and/or conduct of the study
研究组 & 干预措施
AZD9291+ placebo
AZD9291 (80 mg or 40 mg orally, once daily) plus placebo Erlotinib (150mg or 100mg orally, once daily) or placebo Gefitinib (250 mg orally, once daily), in accordance with the randomization schedule.
干预措施: AZD9291 80 mg/40 mg + placebo (Drug)
AZD9291+ placebo
AZD9291 (80 mg or 40 mg orally, once daily) plus placebo Erlotinib (150mg or 100mg orally, once daily) or placebo Gefitinib (250 mg orally, once daily), in accordance with the randomization schedule.
干预措施: Placebo Erlotinib 150/100mg (Drug)
AZD9291+ placebo
AZD9291 (80 mg or 40 mg orally, once daily) plus placebo Erlotinib (150mg or 100mg orally, once daily) or placebo Gefitinib (250 mg orally, once daily), in accordance with the randomization schedule.
干预措施: Placebo Gefitinib 250 mg (Drug)
Standard of Care + placebo AZD9291
Erlotinib (150 mg or 100 mg orally, once daily) or placebo Gefitinib (250 mg orally, once daily) plus placebo AZD9291 (80 mg or 40 mg orally, once daily), in accordance with the randomisation schedule.
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).
干预措施: Placebo AZD9291 80 mg/ 40 mg (Drug)
Standard of Care + placebo AZD9291
Erlotinib (150 mg or 100 mg orally, once daily) or placebo Gefitinib (250 mg orally, once daily) plus placebo AZD9291 (80 mg or 40 mg orally, once daily), in accordance with the randomisation schedule.
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).
干预措施: Erlotinib 150/100 mg (Drug)
Standard of Care + placebo AZD9291
Erlotinib (150 mg or 100 mg orally, once daily) or placebo Gefitinib (250 mg orally, once daily) plus placebo AZD9291 (80 mg or 40 mg orally, once daily), in accordance with the randomisation schedule.
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).
干预措施: Gefitinib 250 mg (Drug)
结局指标
主要结局
Median Progression Free Survival (PFS) (Months)
时间窗: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression
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.
Percentage of Participants in Progression Free Survival at 6, 12, and 18 Months
时间窗: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression
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.
次要结局
- Disease Control Rate (DCR)(At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression)
- Depth of Response(At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression)
- Overall Survival (OS)- Number of Participants With an Event(From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 29 months))
- Objective Response Rate (ORR)(At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression)
- Duration of Response (DoR)(At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression)
- Plasma Concentrations of AZD9291(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))
- Participants Reported Outcome by Cancer Therapy Satisfaction Questionnaire 16 Items (CTSQ-16 Questionnaire)(Questionnaire completed in cycle 2 and 3, prior to Week 6 scan (approximately 2 months))
- Plasma Concentrations of Metabolites 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))
- Plasma Concentrations of 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))
- Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ) Questionnaires Lung Cancer 13 (QLQ-LC13)(Questionnaires completed at baseline, first 9 months, and at week 1, 2, 3, 4, 5, 6, 12, 18, 24, 30 and 36)
- Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30)(Questionnaires completed at baseline, first 9 months, and at week 6, 12, 18, 24, 30, and 36.)