Combination of Osimertinib and Aspirin to Treat 1st Generation Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor（EGFR-TKI）Resistance Non-small Cell Lung Cancer ( NSCLC)
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|ClinicalTrials.gov Identifier: NCT03543683|
Recruitment Status : Not yet recruiting
First Posted : June 1, 2018
Last Update Posted : June 1, 2018
|Condition or disease||Intervention/treatment||Phase|
|Non-Small Cell Lung Cancer Stage IIIB Non-small Cell Lung Cancer Stage IV EGFR T790M||Drug: Osimertinib Drug: Aspirin||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||200 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase II,Single-arm Study to Evaluate the Efficacy of the Combination of Osimertinib and Aspirin in Patients With Disease Progression to 1st Generation EGFR-TKI Due to Acquisition of EGFR T790M|
|Estimated Study Start Date :||July 1, 2018|
|Estimated Primary Completion Date :||June 30, 2019|
|Estimated Study Completion Date :||June 30, 2021|
Experimental: 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.
Osimertinib, also known as azd9291, is a 3rd-generation EGFR-TKI used to treat NSCLC patients with resistance to 1st generation EGFR-TKI due to T790M mutation. It has been approved in clinical applications by the FDA in 2015.
Other Name: OSI
Aspirin, also known as acetylsalicylic acid (ASA), is a very safe medication used to treat pain, fever, or inflammation.
Other Name: ASP
- 1-year median progression-free survival（PFS） rates according to resist 1.1 [ Time Frame: 3years ]To evaluate the response to therapy and 1 year median 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 .
- median PFS according to resist 1.1 [ Time Frame: 3years ]To evaluate the response to therapy and 1 year progression-free survival (PFS) 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 .
- median overall survival(OS) according to resist 1.1 [ Time Frame: 3years ]To evaluate the response to therapy and overall survival(OS) 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
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Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03543683
|Contact: He Yong, firstname.lastname@example.org|