An Open Label, Multicenter, Phase II Study of AZD9291 in Non-small Cell Lung Cancer (NSCLC) Patients Harboring T790M Mutation Who Failed EGFR TKIs and With Brain and/or Leptomeningeal Metastasis
试验速览
- 阶段
- 2 期
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- Overall response rate (ORR) in CNS -brain metastasis cohort
研究概览
简要总结
AZD9291 is an oral potent irreversible EGFR TKI selective for sensitizing EGFR mutation and T790M resistance mutation but sparing wild-type EGFR. Preclinical studies indicate that AZD9291 has significant exposure in the brain and activity against EGFR mutant brain metastasis. In addition, anti-tumor activities of AZD9291 in patients with advanced stage EGFR mutant NSCLC including patients with brain metastasis have been reported in an ongoing Phase I study. More recently, AZD9291 at a dose of 160mg also showed promising efficacy in heavily pre-treated patients with leptomeningeal disease from EGFR mutant NSCLC. Among 11 evaluable for response, 6 patients had LM imaging improvement and 3 out of 7 patients with abnormal neurological exam at baseline had symptomatic improvement. Compared to AZD9291, other 3rd generation EGFR TKIs, rociletinib or HM61713 has not been reported to be effective in most of CNS disease of NSCLC. Further, previous studies with AZD9291 showed anecdotal case series or undetermined for T790M mutation status, indicating more systematic study is warranted.
Based on these data, the investigators are going to conduct phase II study of AZD9291 in NSCLC patients harboring T790M mutation who failed EGFR TKIs and brain and/or leptomeningeal metastasis.
详细描述
- Primary end points
- Overall response rate (ORR) in CNS -brain metastasis cohort
- Overall survival - Leptomeningeal with or without brain metastasis cohort
- Secondary end points
- Whole body disease control rate (DCR)
- Time to brain progression
- Progression free survival (PFS) in BM cohort
- Overall survival (OS)
- Adverse events (AEs)
- Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal fluid (CSF)
- Treatment AZD9291 160mg po daily (1 cycle of 28 days)
- Total patient sample size Eligible patients will be divided into two cohorts, brain metastasis (BM) cohort and leptomeningeal metastasis (LM) with or without BM cohort. The two patient cohorts use different primary endpoints.
- BM cohort For the BM cohort, the primary outcome is overall response (CR+PR). Let P denote the overall response rate of AZD9291. From some preliminary data of response in the brain or leptomeningeal seeding with AZD 9291 in phase II AURA and BLOOM study, we hypothesized that H0:P= 10% and H1:P =30%. The BM cohort uses Simon's optimal two-stage design as follows.
Stage 1: Treat n1 = 18 patients. If r1 = 2 or fewer patients respond, stop the BM cohort concluding that the study therapy is inefficacious. Otherwise, proceed to Stage 2.
Stage 2: Treat additional n2 = 17 patients. If r = 6 or fewer patients respond among the cumulative n1 + n2 = 35 patients, then conclude that the study therapy is inefficacious. Otherwise, accept the study therapy for further investigation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •EGFR activating mutant NSCLC patients who failed EGFR TKIs (gefitinib, erlotinib, or afatinib) and develop CNS disease (BM and/or LM) with T790M mutation either tissue or plasma. For patients with intracranial progression, prior radiation therapy is not mandatory. Extracranial progression is allowed.
- •Patients who failed to 3rd generation EGFR TKIs (AZD9291 (80mg), Rociletinib, HM61713) and develop CNS progression but stable extracranial disease
- •Age ≥18 years
- •ECOG performance status of 0 to 2
- •For BM, at least one measurable intracranial lesion as ≥ 10mm in the longest diameter by magnetic resonance imaging (MRI)
- •For LM, at least one site of CNS leptomeningeal disease that can be assessed by MRI
- •Adequate organ function as evidenced by the following;
- •Absolute neutrophil count > 1.5 x 109/L;
- •platelets > 100 x 109/L;
- •total bilirubin ≤1.5 UNL;
- •AST and/or ALT < 5 UNL;
- •CCr ≥ 50mL/min.
- •Female subjects must either be of non-reproductive potential
- •Subject is willing and able to comply with the protocol
- •Signed written informed consent
排除标准
- •Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 1 week
- •Any unresolved toxicities from prior therapy, greater than CTCAE grade 1
- •Mean QT interval corrected for heart rate (QTc) ≥ 470 ms
- •Uncontrolled systemic illness including uncontrolled hypertension, active bleeding, or active infection.
- •Past medical history of interstitial lung disease, drug induced interstitial lung disease, radiation pneumonitis which required steroid treatment
- •History of hypersensitivity to AZD9291
- •Known intracranial haemorrahge which is unrelated to tumor Refractory nausea and vomiting
研究组 & 干预措施
AZD9291 in BM or LM cohort in T790M positive
- Brain metastasis cohort (BM cohort)
- Leptomeningeal metastasis cohort (LM cohort)
干预措施: AZD9291 (Drug)
结局指标
主要结局
Overall response rate (ORR) in CNS -brain metastasis cohort
时间窗: December, 2019 (one-year follow-up from last patient -in)
At least one visit response of CR (complete response) or PR (partial response) that is confirmed at least 4 weeks later by using RECIST 1.1 criteria
Overall survival - Leptomeningeal with or without brain metastasis cohort
时间窗: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
From the date of study start to the date of all cause death
次要结局
- Adverse events (AEs)(December, 2019 (one-year follow-up from last patient -in))
- Overall survival (OS)(December, 2019 (one-year follow-up from last patient -in))
- Exploratory analysis of EGFR mutation/T790M(December, 2019 (one-year follow-up from last patient -in))
- Whole body disease control rate (DCR)(December, 2019 (one-year follow-up from last patient -in))
- Time to brain progression(December, 2019 (one-year follow-up from last patient -in))
- Progression free survival (PFS) in BM cohort(December, 2019 (one-year follow-up from last patient -in))
研究者
Myung-Ju Ahn
Professor
Samsung Medical Center