A Phase II Trial of Pemetrexed (Alimta [Registered Trademark]) Combined With Sirolimus (Rapamycin, Rapamune [Registered Trademark]) in Subjects With Relapsed or Refractory NSCLC
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 42
- 试验地点
- 1
- 主要终点
- Phase II: Clinical Response Rate
研究概览
简要总结
Background:
The drug pemetrexed is used to treat non-small cell lung cancer (NSCLC) that does not respond to standard therapy or that has recurred after standard therapy; however, only 9 in 100 patients respond to pemetrexed.
Sirolimus is a drug that blocks a protein in cells called mammalian target of rapamycin (mTOR). In cancer cells, mTOR is active when it should not be, allowing the cells to grow uncontrollably. This protein is unusually active in many cases of NSCLC. By blocking the activity of mTOR, sirolimus may make the cancer cells more responsive to treatment with pemetrexed.
Objectives:
To determine if sirolimus in combination with pemetrexed is safe and well tolerated in patients with NSCLC.
To determine the highest safe dose of pemetrexed combined with sirolimus.
To look at the ability of sirolimus and pemetrexed to fight NSCLC.
To learn how the body eliminates sirolimus and pemetrexed.
Eligibility:
Patients 18 years of age and older with NSCLC whose disease does not respond to standard therapy or has recurred after treatment with standard therapy.
Design:
Biopsy before treatment starts, if the tumor is easy to reach by bronchoscopy or can be done by needle biopsy. This procedure is optional.
Drug treatment, as follows:
- Day 1: Intravenous (through a vein) infusions of pemetrexed. Small groups (3 to 6) of patients are given pemetrexed at a certain dose level. If the first group experiences no significant side effects, the next group receives a higher dose. This continues in succeeding groups for up to five dose levels until the maximum tolerated study dose (highest dose that patients can be given safely) is determined.
- To lessen the side effects of pemetrexed, patients also receive a Vitamin B12 injection every 21 days, folic acid tablets daily, and dexamethasone tablets twice a day the day before, the day of, and the day after pemetrexed infusions.
- Days 1-21: Sirolimus tablets by mouth.
Evaluations during the treatment period:
- History and physical examinations, blood and urine tests, electrocardiogram.
- Disease evaluation with computed tomography (CT), positron emission tomography (PET) or magnetic resonance scans (MRI) scans....
详细描述
Background:
- Lung cancer is the most deadly cancer due to late stage of diagnosis and intrinsic resistance to chemotherapy.
- Pemetrexed is a well tolerated Food and Drug Administration (FDA)-approved second line chemotherapeutic agent with a 9% response rate.
- Increasing the efficacy of pemetrexed could provide clinical benefit for patients with refractory NSCLC.
- Inhibition of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mTOR pathway may increase response to chemotherapy.
- Combining sirolimus, an mTOR inhibitor, with pemetrexed could improve patient outcomes.
Objectives:
- Determine the safety, tolerability, pharmacokinetics (PKs), and maximum tolerated dose (MTD) of the combination of sirolimus with pemetrexed in subjects with NSCLC subjects with activation of the Akt/mTOR pathway.
- Determine the clinical response rate at the MTD of sirolimus plus pemetrexed in NSCLC subjects.
- Determine effects of sirolimus on activation of the PI3K/Akt/mTOR pathway in peripheral blood mononuclear cells (PBMCs) and/or tumor tissues, to determine metabolic changes using PET scans, and measure PKs.
Eligibility:
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Treatment level 4 - 10 mg load
Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2
干预措施: Pemetrexed (Drug)
Treatment level 1 - 3mg load
Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m^2
干预措施: FDG-PET (Drug)
Treatment level 1 - 3mg load
Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m^2
干预措施: Pemetrexed (Drug)
Treatment level 1 - 3mg load
Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m^2
干预措施: Sirolimus (Drug)
Treatment level 1 - 3mg load
Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m^2
干预措施: Vitamin B12 (Dietary Supplement)
Treatment level 1 - 3mg load
Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m^2
干预措施: Folic acid tablets (Dietary Supplement)
Treatment level 1 - 3mg load
Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m^2
干预措施: Dexamethasone tablets (Drug)
Treatment level 2 - 6 mg load
Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2
干预措施: FDG-PET (Drug)
Treatment level 2 - 6 mg load
Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2
干预措施: Pemetrexed (Drug)
Treatment level 2 - 6 mg load
Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2
干预措施: Sirolimus (Drug)
Treatment level 2 - 6 mg load
Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2
干预措施: Vitamin B12 (Dietary Supplement)
Treatment level 2 - 6 mg load
Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2
干预措施: Folic acid tablets (Dietary Supplement)
Treatment level 2 - 6 mg load
Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2
干预措施: Dexamethasone tablets (Drug)
Treatment level 3 - 6mg load
Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2
干预措施: FDG-PET (Drug)
Treatment level 3 - 6mg load
Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2
干预措施: Pemetrexed (Drug)
Treatment level 3 - 6mg load
Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2
干预措施: Sirolimus (Drug)
Treatment level 3 - 6mg load
Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2
干预措施: Vitamin B12 (Dietary Supplement)
Treatment level 3 - 6mg load
Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2
干预措施: Folic acid tablets (Dietary Supplement)
Treatment level 3 - 6mg load
Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2
干预措施: Dexamethasone tablets (Drug)
Treatment level 4 - 10 mg load
Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2
干预措施: FDG-PET (Drug)
Treatment level 4 - 10 mg load
Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2
干预措施: Sirolimus (Drug)
Treatment level 4 - 10 mg load
Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2
干预措施: Vitamin B12 (Dietary Supplement)
Treatment level 4 - 10 mg load
Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2
干预措施: Folic acid tablets (Dietary Supplement)
Treatment level 4 - 10 mg load
Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2
干预措施: Dexamethasone tablets (Drug)
Treatment level 5 - 15 mg load
Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m^2
干预措施: FDG-PET (Drug)
Treatment level 5 - 15 mg load
Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m^2
干预措施: Pemetrexed (Drug)
Treatment level 5 - 15 mg load
Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m^2
干预措施: Sirolimus (Drug)
Treatment level 5 - 15 mg load
Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m^2
干预措施: Vitamin B12 (Dietary Supplement)
Treatment level 5 - 15 mg load
Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m^2
干预措施: Folic acid tablets (Dietary Supplement)
Treatment level 5 - 15 mg load
Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m^2
干预措施: Dexamethasone tablets (Drug)
结局指标
主要结局
Phase II: Clinical Response Rate
时间窗: 21 weeks
Clinical response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Partial response (PR) at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Phase I: Maximum Tolerated Dose (MTD) of Pemetrexed
时间窗: 5 weeks
The phase I component of the study are to determine the safety and tolerability of pemetrexed in human subjects with non small cell lung cancer (NSCLC), and to determine the maximum tolerated dose.
Phase I: Maximum Tolerated Dose (MTD) of Sirolimus
时间窗: 5 weeks
The phase I component of the study are to determine the safety and tolerability of sirolimus in human subjects with non small cell lung cancer (NSCLC), and to determine the maximum tolerated dose.
次要结局
- Number of Participants With Serious and Non-Serious Adverse Events(Date treatment consent signed to date off study, approximately 45 months)
研究者
Arun Rajan, M.D.
Principal Investigator
National Cancer Institute (NCI)