Phase I/II Study With the Combination of Afatinib and Selumetinib in Advanced KRAS Mutant Positive and PIK3CA Wildtype Non-small Cell Lung Cancer
试验速览
- 阶段
- 1 期
- 入组人数
- 320
- 试验地点
- 2
- 主要终点
- Dose Limiting Toxicities (Phase I)
研究概览
简要总结
This is a multi-center open-label proof-of-concept study consisting of two parts: PART A - a phase I dose-finding study (3 + 3 classical design) evaluating the RP2D of afatinib in combination with selumetinib in KRASm NSCLC; and PART B - a randomized phase II study investigating the progression free survival and safety of selumetinib/afatinib combination therapy compared to standard of care chemotherapy in KRASm NSCLC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 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
- •Histological or cytological proof of advanced NSCLC; for PART B: treated with first line therapy for metastatic disease only.
- •Written documentation of a known pathogenic KRAS (exon 2, 3 or 4) mutation and PIK3CA wildtype (defined as absence of mutations in exon 9 and 20)
- •Able and willing to give written informed consent
- •Able and willing to undergo blood sampling for PK and PD analysis
- •Life expectancy >=3 months allowing adequate follow up of toxicity evaluation and antitumor activity.
- •WHO performance status of 0 or
- •Able and willing to undergo a tumor biopsies prior to start, after two weeks (part A only) and upon progression of disease
- •Measurable disease according to RECIST 1.1
- •Adequate organ system function measured by laboratory values
排除标准
- •Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment.
- •History of another malignancy Exception PART A: Patients who have been disease-free for at least 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent second malignancies are eligible. Exception PART B: Adequately treated carcinoma in situ of the cervix and adequately treated basal cell carcinoma of the skin.
- •Symptomatic or untreated leptomeningeal disease.
- •Symptomatic brain metastasis.
- •Patients previously treated with any drug combination known to interfere with EGFR, HER2, HER3, HER4 or MAPK- and PI3K-pathway components, including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK and ERK.
- •History of interstitial lung disease or pneumonitis
- •Radio-, immuno- or chemotherapy within the last 2 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed.
- •Opthalmological diseases
- •Patients with left ventricular ejection fraction (LVEF) < 55%
- •Patients with cardiac comorbidities
- •Concomitant or recent use (in the past 14 days) of strong inhibitors and inducers of CYP1A2, CYP2C19, CYP3A4, 3A5 and P-glycoprotein (P-gp)
研究组 & 干预措施
Afatinib plus selumetinib
Combination of afatinib and selumetinib at the optimal dose and regimen as determined in the phase I part of this study
干预措施: Afatinib (Drug)
Afatinib plus selumetinib
Combination of afatinib and selumetinib at the optimal dose and regimen as determined in the phase I part of this study
干预措施: Selumetinib (Drug)
Control
Standard-of-care second line treatment for non small cell lung cancer (docetaxel)
干预措施: Docetaxel (Drug)
结局指标
主要结局
Dose Limiting Toxicities (Phase I)
时间窗: Cycle 1 (4 weeks)
Incidence of DLTs in the first treatment cycle
Progression Free Survival (Phase II)
时间窗: CT scan every 6 weeks and monthly phone call until start of subsequent anticancer therapy or until all patients have been followed up for at least 18 months of have been lost to follow up, whichever occurs first
PFS measured by RECIST v 1.1
次要结局
- Tolerability (Incidence and severity of adverse events per CTCAE v4.03)(Up to 28 days after last study drug intake)
- Plasma concentrations of afatanib and selumetinib(On day 1, 2, 4, 8, 15, 22 in cycle 1, on day 1 and 2 in cycle 2 and subsequently at every treatment cycle pre-dose)
- Efficacy (Phase II) (Overall response rate (ORR), duration of response (DOR) , time to response (TTR) and overall survival (OS) per RECIST v1.1)(Assessed by CT scans every 6 weeks and by monthly phone call until all patients have been followed up for at least 18 months or have been lost to follow up, whichever occurs first.)