NCT02856893已完成2 期
APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR Mutant NSCLC Patients
European Organisation for Research and Treatment of Cancer - EORTC41 个研究点 分布在 6 个国家目标入组 156 人开始时间: 2017年10月10日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 156
- 试验地点
- 41
- 主要终点
- PFS Rate at 18 Months
研究概览
简要总结
The phase II APPLE trial gives the opportunity to prospectively validate liquid biopsies as a new standard for testing tumor progression compared with conventional radiological procedure in EGFR mutant advanced NSCLC patients. Moreover based on the sequential T790M test during treatment the investigators will assess the predictive value of liquid biopsies. APPLE trial will examine the best strategy for delivering osimertinib (upfront versus sequential treatment after 1st generation EGFR TKI) in EGFR mutant NSCLC patients. Finally, the trial will also explore the mechanisms of acquired resistance to Osimertinib based on the results of an optional biopsy upon progression.
详细描述
Primary objective To evaluate the best strategy for delivering Osimertinib (AZD9291) in NSCLC patients with EGFR mutation. The objective is assessed by Progression Free Survival rate at 18 months (PFSR-OSI-18).
Secondary objectives
- To evaluate PFS while receiving osimertinib measured from randomization by RECIST criteria 1.1.
- To evaluate PFS measured from switching to osimertinib by RECIST criteria 1.1.
- To determine the proportion of patients receiving osimertinib based on the determination of cfDNA T790M mutation positive.
- To evaluate PFS-2.
- To evaluate Overall Response Rate (ORR) to osimertinib.
- To evaluate the Treatment duration.
- To evaluate Time to progression (TTP) on osimertinib (measured from switching to osimertinib).
- To evaluate Overall Survival (OS).
- To evaluate brain progression free survival (BPFS).
- Safety.
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
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Registration:
- •Pathological diagnosis of adenocarcinoma of the lung carrying common EGFR activating mutations associated with EGFR-TKI sensitivity (Del19 or L858R); performed locally; no other EGFR mutations will be allowed. In case of other (than EGFR) concomitant mutations, discussion with EORTC Headquarters is mandatory;
- •Stage IV NSCLC;
- •Blood sample available for cfDNA EGFR T790M central testing;
- •Age ≥18 years;
- •EGFR TKI treatment-naïve eligible to receive first-line treatment with EGFR TKI;
- •Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy, investigational agents) if performed more than 12 months before registration;
- •Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations
- •Randomization:
- •Report of adequacy sample for cfDNA EGFR T790M test by central laboratory;
- •Prior palliative radiotherapy or surgery are allowed if completed at least 4 weeks before the randomization;
- •Patients with brain metastases are allowed provided they are stable (i.e. without evidence of progression by imaging for at least two weeks prior to the first dose of trial treatment and without deterioration of any neurologic symptoms), and have not received steroids for at least 7 days before randomization; Baseline tumor assessment scans are done within 21 days before randomization;
- •Evaluable disease as defined below;
- •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 computed tomography (CT) or magnetic resonance imaging (MRI), and which is suitable for accurate repeated measurements.
- •WHO Performance Status 0-2, with no clinically significant deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks;
- •Adequate bone marrow, renal, hepatic and liver function within 21 days from randomization and defined as follows:
- •Absolute neutrophil count ≥1.5 x 109/L;
- •Platelet count ≥100 x 109/L;
- •Haemoglobin ≥9 g/dL;
- •Alanine aminotransferase (ALT) ≤2.5x the upper limit of normal (ULN) if no demonstrable liver metastases or ≤5xULN in the presence of liver metastases;
- •Aspartate aminotransferase (AST) ≤2.5xULN if no demonstrable liver metastases or ≤5xULN in the presence of liver metastases;
- •Total bilirubin ≤1.5xULN if no liver metastases or ≤3xULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases;
- •Serum creatinine ≤1.5xULN concurrent with creatinine clearance ≥50 mL/min (measured or calculated by Cockcroft and Gault equation);
- •No significant comorbidity that according to the investigator would hamper the participation on the trial;
- •Female patients should be using adequate contraceptive measures, should not be breastfeeding, until 12 months after the last dose, and must have a negative pregnancy test (serum or urine) prior to first dose of study drug (within 72 hours); or female patients must have an evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
- •Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
- •Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution.
- •Documentation of irreversible surgical sterilisation by hysterectomy, bilateraloophorectomy, or bilateral salpingectomy but not tubal ligation.
- •Male patients should be willing to use barrier contraception, i.e., condoms
- •o Male patients will be advised to arrange for the freezing of sperm samples prior to the start of the study should they wish to father children, and not to donate sperm until 6 months after discontinuation of study treatment." (as per Investigator Brochure, IB)
- •Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
排除标准
- •Treatment with any of the following:
- •Prior treatment with any systemic anti-cancer therapy for locally advanced/metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug;
- •Prior treatment with an EGFR-TKI;
- •Major surgery (excluding placement of vascular access) within 4 weeks before randomization;
- •Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks before randomization
- •Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of study drug) medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A4;
- •Other anti-cancer therapies and alternative medications such as homeopathic treatment, etc;
- •Treatment with an investigational drug within five half-lives of the compound or any of its related material, if known;
- •Leptomeningeal carcinomatosis; spinal cord compression;
- •Any unresolved toxicities from prior systemic therapy (e.g., adjuvant chemotherapy) greater than CTCAE grade 2 at the time of randomization;
- •Patients will not be eligible if they have evidence of active malignancy (other than non-melanoma skin cancer or localized cervical cancer or localised and presumed cured prostatic cancer) within 2 years before randomization and are not receiving specific treatment for these malignancies at baseline assessment;
- •Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Active infection will include any patients receiving intravenous treatment for infection; active hepatitis B infection will, at a minimum, include all patients who are Hepatitis B surface antigen positive (HbsAg positive) based on serology assessment. Screening for chronic conditions is not required;
- •Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of Osimertinib or Gefitinib;
- •Any of the following cardiac criteria:
- •Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs using local clinic ECG machine-derived QTcF value
- •Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250 msec or history of episodes of bradycardia (<50 BPM);
- •Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval.
- •Abnormal cardiac function: LVEF < 50% (assessed by MUGA or ECHO)
- •Past medical history of ILD (Interstitial Lung Disease), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
研究组 & 干预措施
Gefitinib till + blood test/progression than Osimertinib
Experimental
Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1
干预措施: Gefitinib (Drug)
Osimertinib till progression
Experimental
Osimertinib until PD according to RECIST 1.1
干预措施: Osimertinib (Drug)
Gefitinib till + blood test/progression than Osimertinib
Experimental
Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1
干预措施: Osimertinib (Drug)
Gefitinib till progression than Osimertinib
Active Comparator
Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1
干预措施: Osimertinib (Drug)
Gefitinib till progression than Osimertinib
Active Comparator
Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1
干预措施: Gefitinib (Drug)
结局指标
主要结局
PFS Rate at 18 Months
时间窗: 18 months after randomization
The primary endpoint is defined as the proportion of patients at 18 months who are alive and did not experience an event for PFS by RECIST 1.1 while receiving osimertinib (PFS-OSI). Specifically, it relates to progression of disease according to RECIST 1.1 or death after switching to osimertinib in arms "Gefitinib till + blood test/progression then Osimertinib" and "Gefitinib till progression then Osimertinib". It is formally assessed in these two arms, whilst only provided as a reference for the "Osimertinib till progression" arm, in which progression of disease or death is measured from baseline considering that patients start with osimertinib.
次要结局
- PFS While Receiving Osimertinib by RECIST Criteria 1.1(From randomization till the date of progression on osimertinib or death, an average of 2 years.)
- Proportion of Patients Receiving Osimertinib Based on the Determination of cfDNA T790M Mutation Positive(From randomization till the date of positive cfDNA T790M status or death, on average 2 years.)
- Time to Progression on Osimertinib(From randomization till the date of progression on osimertinib or death, on average 2 years.)
- Overall Response Rate (ORR) to Osimertinib(Time from randomization until end of osimeritinib treatment, or death, on average 2 years.)
- Treatment Duration(From randomization till the date of end of protocol treatment)
- Overall Survival (OS)(From randomization till the date of death)
- Brain Progression Free Survival (BPFS)(From randomization till the date of progression in the brain)
- PFS-2(From randomization till the date of second progression on second line treatment)
研究者
研究点 (41)
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