A Phase III, Multicenter, Randomized, Open-label Study of Oral LDK378 Versus Standard Chemotherapy in Adult Patients With ALK-rearranged (ALK-positive) Advanced Non-small Cell Lung Cancer Who Have Been Treated Previously With Chemotherapy (Platinum Doublet) and Crizotinib
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 231
- 试验地点
- 14
- 主要终点
- Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC)
研究概览
简要总结
The primary purpose of the study was to compare the antitumor activity of LDK378 vs. chemotherapy in patients previously treated with chemotherapy (platinum doublet) and crizotinib. Patients in the chemotherapy arm were given the option to switch to LDK378 after confirmed progressive disease (PD), while also had the choice to continue with pemetrexed treatment.
详细描述
A total of 231 patients were randomized to one of the two treatment arms in a 1:1 ratio. Randomization was stratified by World Health Organization (WHO) performance status (0 versus 1-2) and whether the patient had brain metastases at screening. The study was planned to be ended once the final overall survival (OS) analysis was performed (at the earliest of approximately 196 deaths observed or statistical significance reached at earlier OS interim analysis).
Following an agreement between Novartis and European Medicines Agency (EMA) in May 2023 to terminate the trial earlier, this study was completed when the total number of deaths was 190. Patients who had Response Evaluation Criteria In Solid Tumors (RECIST)-defined disease progression as confirmed by the Blinded Independent Review Committee (BIRC), but who, in the opinion of the Investigator, had continued clinical benefit from study treatment on either the chemotherapy arm or the ceritinib arm, continued to receive treatment. These patients continued assessments in the treatment phase. In addition, only patients randomized to the chemotherapy arm were allowed to crossover to receive ceritinib therapy (extension treatment [ET] phase) after BIRC-confirmed, RECIST-defined disease progression, and provided they met the eligibility requirements.
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 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient has a histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive as assessed by the FDA approved Abbott FISH Test.
- •Patient has stage IIIB or IV diagnosis and must have received one or two prior regimens (including platinum- doublet) of cytotoxic chemotherapy for the treatment of locally advanced or metastatic NSCLC.
- •Patient has at least one measurable lesion as defined by RECIST 1.
- •A previously irradiated site lesion may only be counted as a target lesion if there is clear sign of progression since the irradiation
- •Patients must have received previous treatment with crizotinib for the treatment of locally advanced or metastatic NSCLC.
排除标准
- •Patient with known hypersensitivity to any of the excipients of LDK378 (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate)
- •Patient with a history of severe hypersensitivity reaction to pemetrexed or docetaxel or any known excipients of these drugs.
- •Patient with symptomatic central nervous system (CNS) metastases who is neurologically unstable or has required increasing doses of steroids within the 2 weeks prior to screening to manage CNS symptoms.
研究组 & 干预措施
Ceritinib
Ceritinib 750 mg
干预措施: Ceritinib (Drug)
Chemotherapy
Chemotherapy as determined by BIRC
干预措施: Pemetrexed (Drug)
Chemotherapy
Chemotherapy as determined by BIRC
干预措施: Docetaxel (Drug)
结局指标
主要结局
Progression Free Survival (PFS) Per Blinded Independent Review Committee (BIRC)
时间窗: From the date of randomization to the date of first radiologically documented disease progression or death due to any cause up to approximately 24 months
PFS was defined as the time from the date of randomization to the date of the first radiologically documented disease progression or death due to any cause.
次要结局
- Overall Survival (OS)(Up to approximately 114 months)
- Progression Free Survival (PFS) Per Investigator Assessment(Up to approximately 84 months)
- Overall Response Rate (ORR) Per BIRC(Up to approximately 54 months)
- Overall Response Rate (ORR) Per Investigator Assessment(Up to approximately 93 months)
- Duration of Response (DOR) Per BIRC(Up to approximately 54 months)
- Duration of Response (DOR) Per Investigator Assessment(Up to approximately 93 months)
- Disease Control Rate (DCR) Per BIRC(Up to approximately 54 months)
- Disease Control Rate (DCR) Per Investigator Assessment(Up to approximately 93 months)
- Time to Response (TTR) Per BIRC(Up to approximately 52 weeks)
- Time to Response (TTR) Per Investigator Assessment(Up to approximately 45 weeks)
- Overall Intracranial Response Rate (OIRR) Per BIRC(Up to approximately 18 months)
- Intracranial Disease Control Rate (IDCR) Per BIRC(Up to approximately 18 months)
- Duration of Intracranial Response (DOIR) Per BIRC(Up to approximately 18 months)
- Least Squares Mean Scores on the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQC30)(Screening and treatment phase up to 92 months)
- EORTC QLQ-LC13 Time to Definitive Deterioration(Screening and treatment phase up to 92 months)
- Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS)(Screening and treatment phase up to 92 months)
- Least Squares Mean Scores on the EQ-5D-5L Index(Screening and treatment phase up to 92 months)
- Least Squares Mean Scores on the EQ-5D Visual Analogue Scale (VAS)(Screening and treatment phase up to 92 months)
- Cmax for Ceritinib(Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.)
- Tlast for Ceritinib(Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.)
- Tmax for Ceritinib(Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.)
- AUC0-24h for Ceritinib(Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.)
- Mean Accumulation Ratio (Racc) for Ceritinib(Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.)
- Clearance Rate at Steady State (CLss/F) for Ceritinib(Cycle 1, Day 1 and Cycle 2, Day 1: pre-dose and 1, 2, 4, 6, 8, and 24 hours post-dose. Each cycle was 21 days.)
- Post-Hoc: All Collected Deaths(Pre-treatment and on-treatment deaths: Up to approximately 8 years. Post-treatment survival follow-up deaths: Up to an additional 2.5 years.)