A Phase III Multicenter, Randomized Study of Oral LDK378 Versus Standard Chemotherapy in Previously Untreated Adult Patients With ALK Rearranged (ALK-positive), Stage IIIB or IV, Non-squamous Non-small Cell Lung Cancer
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 376
- 试验地点
- 1
- 主要终点
- Progression Free Survival (PFS) by Blinded Independent Review Committee (BIRC)
研究概览
简要总结
To compare the efficacy and safety of ceritinib with standard first-line chemotherapy (pemetrexed plus cisplatin or carboplatin) in patients with stage IIIB (not candidates for definitive multimodality therapy) or stage IV, non-squamous non-small cell lung cancer (NSCLC) harboring a confirmed anaplastic lymphoma kinase (ALK) rearrangement, using the Ventana immunohistochemistry (IHC) test.
详细描述
This was an open-label, randomized, global, Phase III study that compared the efficacy and safety of ceritinib to standard first-line chemotherapy in patients with advanced (NSCLC) harboring ALK rearrangement. The confirmation of ALK rearrangement was done using the ICH test by a Novartis designated central laboratory. Prior to the study, patients had not received any previous systemic, anti-cancer therapy, including ALK inhibitors, for newly diagnosed advanced non-squamous NSCLC.
The patients were randomized in a 1:1 ratio to either receive ceritinib (750 mg once daily, fasted) or chemotherapy. The chemotherapy regimen consisted of a platinum-based doublet with pemetrexed followed by pemetrexed maintenance in patients without progressive disease after 4 cycles.
Treatment was continued until the blinded independent review committee (BIRC) confirmed disease progression based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), occurrence of unacceptable toxicity, or meeting other discontinuation criteria. Patients in either arm were permitted to continue the assigned study treatment beyond BIRC-confirmed disease progression in case of continued clinical benefit, as determined by the Investigator.
All patients who discontinued treatment during the treatment phase for reasons other than death, lost to follow-up, pregnancy or disease progression entered the post-treatment follow-up period until disease progression, withdrawal of consent or death.
In the chemotherapy arm, patients were allowed to switch and receive ceritinib after BIRC-confirmed disease progression (extension-treatment period).
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
- •The patient had a histologically or cytologically confirmed diagnosis of non-squamous Non-small cell lung cancer (NSCLC) that was Anaplastic lymphoma kinase (ALK) positive as assessed by the Ventana Immunohistochemistry (IHC) test. The test was performed at Novartis designated central laboratories.
- •The patient had a newly diagnosed stage IIIB (who was not a candidate for definitive multimodality therapy) or stage IV NSCLC or relapsed locally advanced or metastatic NSCLC not previously treated with any systemic anti-cancer therapy (e.g. cytotoxic drugs, monoclonal antibody therapy, crizotinib or other ALK inhibitors, or other targeted therapies, either experimental or not), with the exception of neo-adjuvant or adjuvant therapy.
- •The patient had at least one measurable lesion as defined by RECIST 1.
排除标准
- •The patient had known hypersensitivity to any of the excipients of LDK378 (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate).
- •The patient had a history of severe hypersensitivity reaction to platinum-containing drugs, pemetrexed, or any known excipients of these drugs.
- •The patient had symptomatic central nervous system (CNS) metastases and was neurologically unstable or had 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 administered continuously through oral dosing at a dosage of 750 mg once daily in fasted state.
干预措施: Ceritinib (Drug)
Chemotherapy
Pemetrexed plus cisplatin or carboplatin (based on Investigator's choice) for 4 cycles (Induction) followed by pemetrexed as single agent (Maintenance)
干预措施: Pemetrexed (Drug)
Chemotherapy
Pemetrexed plus cisplatin or carboplatin (based on Investigator's choice) for 4 cycles (Induction) followed by pemetrexed as single agent (Maintenance)
干预措施: Cisplatin (Drug)
Chemotherapy
Pemetrexed plus cisplatin or carboplatin (based on Investigator's choice) for 4 cycles (Induction) followed by pemetrexed as single agent (Maintenance)
干预措施: Carboplatin (Drug)
结局指标
主要结局
Progression Free Survival (PFS) by 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 34 months
PFS is defined as the time from the date of randomization to the date of the first radiologically documented disease progression (as assessed by BIRC per RECIST 1.1) or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or had received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. The distribution of PFS was estimated using the Kaplan-Meier (KM) method.
次要结局
- Overall Survival (OS)(From date of randomization to date of death due to any cause, up to approximately 120 months)
- Overall Response Rate (ORR) by BIRC Assessment(Up to approximately 34 months)
- Overall Response Rate (ORR) by Investigator Assessment(Up to approximately 120 months)
- Duration of Response (DOR) by BIRC Assessment(From first documented response to first documented disease progression or death, assessed up to approximately 34 months)
- Duration of Response (DOR) by Investigator Assessment(From first documented response to first documented disease progression or death, assessed up to approximately 120 months)
- Disease Control Rate (DCR) by BIRC Assessment(Up to approximately 34 months)
- Disease Control Rate (DCR) by Investigator Assessment(Up to approximately 120 months)
- Time to Response (TTR) by BIRC Assessment(From randomization to date of first documented response, up to approximately 34 months)
- Time to Response (TTR) by Investigator Assessment(From randomization to date of first documented response, up to approximately 120 months)
- PFS by Investigator Assessment(From the date of randomization to the date of first radiologically documented disease progression or death due to any cause, up to approximately 120 months)
- Overall Intracranial Response Rate (OIRR)(Up to approximately 34 months)
- Intracranial Disease Control Rate (IDCR)(Up to approximately 34 months)
- Duration of Intracranial Response (DOIR)(From first documented response to first documented disease progression in the brain or death, assessed up to approximately 34 months)
- Time to Definitive 10 Point Deterioration in the Composite Endpoint of Pain, Cough or Dyspnea in the European Organization for Research and Treatment of Cancer Quality of Life (EORTC QLQ)- Lung Cancer (LC) 13 Questionnaire(Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months)
- Least Squares Mean Scores on the EORTC-QLQ C30(Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months)
- Least Squares Mean Scores on the Lung Cancer Symptom Scale (LCSS)(Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months)
- Least Squares Mean Scores on the EQ-5D-5L Visual Analogue Score (VAS)(Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months)
- Time to Definitive Deterioration in the Composite Endpoint of Pain, Cough or Dyspnea in the Lung Cancer Symptom Scale (LCSS)(Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months)
- Least Squares Mean Scores on the EORTC QLQ- LC13(Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months)
- Least Squares Mean Scores on the EQ-5D-5L Index(Screening, treatment phase (Cycles 2, 3 then every 2nd cycle until Month 33; after Month 33, every 9 or 12 weeks, end of treatment); follow-up phase (Every 6 weeks until Month 33; after Month 33 every 9 or 12 weeks) up to approximately 120 months)
- Cmax of LDK378(Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days)
- Tmax of LDK378(Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days)
- Tlast of LDK378(Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days)
- AUC0-24 of LDK378(Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose, 1, 2, 4, 6, 8 and 24 hours post-dose. Cycle=21 days)