A Multi-center, Prospective, Non-randomized, Open-label Study of the Efficacy and Safety of Osimertinib Combined with Aspirin in Patients with Locally Advanced or Metastatic Non-small Cell Lung Cancer Who Are T790M-positive and Resistant to First-generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 115
- 试验地点
- 1
- 主要终点
- progression-free survival（PFS） rates according to resist 1.1
研究概览
简要总结
The third generation epidermal growth gactor receptor-tyrosine Kinase Inhibitor（EGFR-TKI） osimertinib has obvious curative effect for EGFR sensitive mutation and T790M mutation(PMID 27959700), but acquired drug resistance will occur. Previous studies show that apoptosis escape can lead to EGFR-TKI resistance.Osimertinib resistant cells show abnormal activation of PI3K/AKT/BIM activation(PMID 28765329). The classical drug aspirin can effectively decrease AKT phosphorylation and activate of BIM(PMID 28881293).So Investigators speculate that aspirin may decrease the PI3K/AKT/BIM signaling pathways, then promote osimertinib resistant cells apoptosis. The current study aims to evaluate the combination of aspirin and osimertinib in patients with EGFR/T790M mutations.
详细描述
Reversible small-molecule EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have shown dramatic therapeutic efficacy in non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations, and have been recommended as the standard first-line therapy in these patients. However, despite excellent initial clinical responses, nearly all patients eventually develop drug resistance after a median period of about 10 months(PMID 26497205). Osimertinib is a 3rd-generation EGFR-TKI used to treat NSCLC patients with resistance to 1st generation EGFR-TKI due to T790M mutation. But Osimertinib also face the problem of acquired drug-resistance(PMID 27959700). Thus, innovative treatment strategies are urgently needed to overcome therapeutic resistance to Osimertinib to improve the survival of patients with NSCLC.
Molecular mechanisms underlying acquired Osimertinib resistance are still not fully understood. Previous study showed that one principal mechanism accounting for majority of acquired resistance to Osimertinib in lung cancer is mediated by an exon 20 C797S mutation etc(PMID 29596911). More molecular mechanisms are still to be found. Apoptosis is a process of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and global mRNA decay. Apoptosis has been found to be related to drug resistance to 1st generation EGFR-TKI(PMID 29731879). The investigators previous found apoptosis is also related to Osimertinib resistance(PMID 28765329). Therefore, promoting apoptosis may be an effective way to improve the response to Osimertinib treatment.
Investigators' group has focused on lung cancer targeted therapy for several years. Previously, investigators have reported that metformin in combination with 1st generation EGFR-TKI could enhance the effect of TKI (PMID 24644001). Therefore, investigators further asked whether the drug combination approach could overcome osimertinib resistance. Aspirin is a widely used and well-tolerated drug for Kawasaki disease, pericarditis, and rheumatic and has arisen keen interest as a potential anticancer agent ever since the report of the clinical evidence that the cancer risk and mortality are reduced in Colon cancer. Aspirin exerts remarkable antitumor properties in tumor cells and mouse models. It strongly inhibited the growth of lung cancer cells, and its combination with TKI agents, including Sorafenib (PMID: 28857200), significantly suppressed RAS-mutant cancers growth and prolonged remission in a xenograft model. Interestingly, Aspirin exposure significantly promoted the apoptosis suggesting that aspirin may overcome Osimertinib resistance by promoting the apoptosis.
Here, investigators'group observed that in clinic, several patients who took osimertinib and aspirin together have shown excellent effect.Investigators therefore conduct this clinical trial to observe whether the combination of Aspirin and Osimertinib could enhance efficacy of Osimertinib in lung cancer patients resistant to 1st generation EGFR-TKI with T790M.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have Histologically or cytologically confirmed non small cell carcinoma of the lung who harbors EGFR-mutation and are previously disease progression to 1st generation EGFR-TKI.
- •Patient must have measurable stage IV disease (includes M1a, M1b stages or recurrent disease) (according to the 7th edition of the tumor node metastasis (TNM) classification system). However, patients with T4NX disease (stage III B) with nodule(s) in ipsilateral lung lobe are not eligible, because such patients were not included in historical controls.
- •Patients be age >18 years and < 75 years.
- •Patients must have a Life Expectancy of greater than 12 weeks.
- •Patients must have an electrocorticography (ECOG) performance status 0 or 1 (Karnofsky > 70).
- •Patients must have normal organ and marrow function as defined below, within one week prior to randomization: absolute neutrophil count >1,500/mL platelets > 100,000/mL total bilirubin: within normal institutional limits AST(SGOT)/ALT(SGPT) < 2.5 X institutional upper limit of normal creatinine < 1.5 X institutional upper limit of normal urine dipstick for proteinuria of < less than 1+. If urine dipstick is > 1+ then a 24 hour urine for protein must demonstrate < 500 mg of protein in 24 hours to allow participation in the study.
- •Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
- •Patients must have an international normalized ratio (INR) < 1.5 and a partial thromboplastin time (PTT) no greater than upper limits of normal within 1 week prior to randomization.
- •Patients with a history of hypertension must be well-controlled (<150 systolic/<100 diastolic) on a stable regimen of anti-hypertensive therapy.
- •Patients must have the ability to understand and the willingness to sign a written informed consent document.
排除标准
- •Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection,symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia,gastric ulcer,hemophilia,thrombopenia,active hemorrhage,podagra,kidney failure or psychiatric illness/social situation that would limit compliance with study requirements.
- •Patients receiving chronic daily treatment with aspirin (> 325 mg/day) or nonsteroidal anti-inflammatory agents known to inhibit platelet function. Treatment with dipyridamole (Persantine), ticlopidine (Ticlid),clopidogrel (Plavix) and/or cilostazol (Pletal)is also not allowed.
- •Patients receiving therapeutic anticoagulation. Prophylactic anticoagulation of venous access devices is allowed provided Section 3.10 is met. Caution should be taken on treating patients with low dose heparin or low molecular weight heparin for DVT prophylaxis during treatment with bevacizumab as there may be an increased risk of bleeding.
- •Prior use of chemotherapy.
- •Patients receiving immunotherapy, hormonal-therapy and or radiotherapy within 2 weeks prior to entering the study. Note: Those who have not recovered from adverse events due to these agents administered will be considered ineligible.
- •Patients receiving any other investigational agents.
- •Patients with uncontrolled brain metastasis. Note: Patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks, and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
- •Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Osimertinib and Aspirin or other agents used in the study are excluded.
- •Women that are pregnant or breastfeeding Note: Pregnant women are excluded from this study because the agents used in this study may be teratogenic to a fetus. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with paclitaxel, breastfeeding women are also excluded from this study.
- •Patients that are HIV-positive on combination antiretroviral therapy due to the potential for lethal infections when treated with marrow-suppressive therapy.
研究组 & 干预措施
osimertinib and aspirin
Osimertinib starting at a dose of 80 mg once a day, orally with meals.The intervention is aspirin which is starting at a dose of 100 mg once a day, orally with meals.Aspirin treatment will be initiated one week before beginning TKI therapy, if possible, but TKI therapy will not be delayed for Aspirin loading. Drug: Osimertinib and Aspirin will be administered once every day. If subject has complete response, partial response, stable disease, or unacceptable toxicity.
干预措施: Osimertinib (Drug)
osimertinib and aspirin
Osimertinib starting at a dose of 80 mg once a day, orally with meals.The intervention is aspirin which is starting at a dose of 100 mg once a day, orally with meals.Aspirin treatment will be initiated one week before beginning TKI therapy, if possible, but TKI therapy will not be delayed for Aspirin loading. Drug: Osimertinib and Aspirin will be administered once every day. If subject has complete response, partial response, stable disease, or unacceptable toxicity.
干预措施: Aspirin (Drug)
osimertinib
Osimertinib starting at a dose of 80 mg once a day, orally with meals. Drug: Osimertinib will be administered once every day. If subject has complete response, partial response, stable disease, or unacceptable toxicity.
干预措施: Osimertinib (Drug)
结局指标
主要结局
progression-free survival（PFS） rates according to resist 1.1
时间窗: 3years
To evaluate the response to therapy and progression-free survival（PFS） rates of the combination of Osimertinib and Aspirin in patients who harbors T790M EGFR-mutant with metastatic pulmonary adenocarcinoma disease progression to 1st generation EGFR-TKI .
次要结局
- median overall survival(OS) according to resist 1.1(3years)
研究者
Yong He
Professor
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University