A Randomized Phase II Study of Paclitaxel-carboplatin-bevacizumab With or Without Nitroglycerin Patches in Patients With Stage IV Non-squamous-non-small Cell Lung Cancer: NVALT12
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 223
- 试验地点
- 8
- 主要终点
- progression free survival
研究概览
简要总结
This study is designed to assess the effects of adding nitroglycerin (NTG) patches, delivery 25 mg NTG per 24 h, to the standard first line treatment of metastatic non-squamous non-small cell lung cancer (NSCLC), i.e. 4 cycles of carboplatin-paclitaxel-bevacizumab, followed by bevacizumab alone until disease progression. Tumor hypoxia is a common phenomenon in lung cancer; it is a known poor prognostic marker, related to treatment resistance. Pre-clinical studies have shown that nitric oxide (NO) donating drugs may decrease hypoxia related drug resistance. NTG is a NO donating drug. NTG increases tumor blood flow and thereby augments antitumor drug delivery to the tumor.
A randomized phase II has shown an increase in the response rate from 42% to 72%, when NTG patches (25 mg/day, day -2 to +3) were added to vinorelbine/cisplatin in patients with advanced NSCLC. In addition, the time to progression increased from 185 to 327 days.
The hypothesis of the present study is that adding NTG transdermal patches to bevacizumab containing chemotherapy improves progression free survival, response rate and overall survival in patients with metastatic non-squamous NSCLC.
详细描述
Standard treatment for non-small cell lung cancer (NSCLC) consists of platinum-containing chemotherapy. It has been shown that the addition of bevacizumab to standard chemotherapy improves progression-free survival (PFS) and overall survival (OS) in patients with non-squamous NSCLC. There is a need for improved PFS and OS and response rates to chemotherapy are only 25-35%.
Tumor hypoxia is a common phenomenon in lung cancer; it is a known poor prognostic marker, related to treatment resistance. Hypoxia Inducible Factor (HIF) -1α is the major factor regulating the response to hypoxia.
HIF directly activates vascular endothelial growth factor (VEGF) and VEGF-receptor. Bevacizumab interacts with this pathway by blocking VEGF.
Pre-clinical studies have shown that nitric oxide (NO) donating drugs may decrease hypoxia related drug resistance. Nitroglycerin (NTG) is a NO donating drug. NTG increases tumor blood flow and thereby augments antitumor drug delivery to the tumor and inhibits HIF-1α.
Interestingly, it has recently been shown in mouse models that the addition of HIF-1α inhibitors to bevacizumab significantly inhibits tumor growth by inducing apoptosis.
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
- •Histologically/cytologically proven stage IV non-squamous NSCLC (according to IASLC staging 7.0)
- •No prior chemotherapy or therapy with systemic anti-tumor therapy (e.g., monoclonal antibody therapy) or prior exposure to agents directed at the HER axis (e.g. epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI), Herceptin). Prior surgery and/or localized palliative irradiation is permitted provided that the irradiated lesion is not the only measurable lesion. Prior adjuvant chemotherapy > 1 year ago and prior treatment with an EGFR-TKI for patients with an activating EGFR mutation is allowed.
- •Age ≥ 18 years.
- •ECOG Performance Status of 0 -
- •Life expectancy of at least 12 weeks.
- •Subjects with at least one uni-dimensional(for RECIST) measurable lesion.
- •Adequate bone marrow, liver and renal function.
- •Adequate non-hormonal contraception for females of childbearing potential during the study and in the 6 months thereafter.
- •Adequate contraception for male participants (or their partners) during the study and in the 6 months thereafter.
排除标准
- •Clinically significant (i.e. active) cardiovascular disease: congestive heart failure >NYHA class 2; CVA or myocardial infarction < 6 months prior to study entry; uncontrolled hypertension (blood pressure systolic > 150 mmHg and/or diastolic > 100 mmHg).
- •Symptomatic hypotension.
- •History of hemoptysis at least grade 2 (bright red blood of at least 2,5 ml in the last 3 months)
- •Evidence of tumor invading major blood vessels on imaging (i.e. superior vena cava or pulmonary artery).
- •History of HIV infection or chronic hepatitis B or C.
- •Active clinically serious infection
- •Symptomatic metastatic brain or meningeal tumors. Patients with brain metastasis may be included the patient is treated with brain radiotherapy and asymptomatic.
- •History of organ allograft.
- •Patients with evidence or history of bleeding diathesis.
- •Non-healing wound or ulcer.
- •History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of enrolment
- •Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of study entry
- •Radiotherapy within 4 weeks of start of study drug. Palliative radiotherapy for bone lesions is allowed > 14 days of start of chemotherapy. Major surgery within 4 weeks of start of study.
- •Use of vasodilators (including 5-phosphodiesterase inhibitors, calcium antagonists or nitrates)
- •Autologous bone marrow transplant or stem cell rescue within 4 months of study
- •Investigational drug therapy outside of this trial during or within 4 weeks of study entry
- •Pregnancy or lactation.
研究组 & 干预措施
carboplatin-paclitaxel-bevacizumab
paclitaxel 200 mg/m2 d1 - carboplatin area under the curve (AUC) 6 d1 - bevacizumab 15 mg/kg d1. Cycles every 3 weeks. Paclitaxel and carboplatin 4 cycles. Bevacizumab till progression
干预措施: carboplatin paclitaxel bevacizumab (Drug)
standard treatment plus nitroglycerin
paclitaxel 200 mg/m2 d1 - carboplatin AUC 6 d1 - bevacizumab 15 mg/kg d1. Cycles every 3 weeks. Paclitaxel and carboplatin 4 cycles. Bevacizumab till progression. Plus nitroglycerin transdermal patches 25 mg per day from day -3 till +2 of First combination cycle till the last bevacizumab monotherapy cycle
干预措施: Standard treatment plus nitroglycerin (Drug)
结局指标
主要结局
progression free survival
时间窗: every 6 weeks during chemotherapy
Imaging
次要结局
- safety of the treatment(every 3 weeks during chemotherapy)
- prediction of early response(after 3 weeks)
- decreased hypoxia(after 6 weeks)
- objective response rate(every 6 weeks during chemotherapy)
- disease control rate(every 6 weeks during chemotherapy)
- duration of response(every 6 weeks during chemotherapy)