Clinical Trials /

Combination of Osimertinib and Aspirin to Treat Osimertinib Resistance Non-small Cell Lung Cancer ( NSCLC)

NCT03532698

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination of Osimertinib and Aspirin to Treat Osimertinib Resistance Non-small Cell Lung Cancer ( NSCLC)
  • 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 3st Generation Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor(EGFR-TKI) Osimertinib

Clinical Trial IDs

  • ORG STUDY ID: COAST 2
  • NCT ID: NCT03532698

Conditions

  • Non-Small Cell Lung Cancer Stage IIIB
  • Non-small Cell Lung Cancer Stage IV
  • EGFR T790M

Interventions

DrugSynonymsArms
AspirinASPosimertinib and aspirin
OsimertinibOSIosimertinib and aspirin

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
osimertinib and aspirinExperimentalOsimertinib and Aspirin starting at a dose of 80 mg and 100mg 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.
  • Aspirin
  • Osimertinib

Eligibility Criteria

        Inclusion Criteria:

        •Patients must have Histologically or cytologically confirmed non small cell carcinoma of
        the lung who harbors EGFR-mutation and are previously disease progression to 3st generation
        EGFR-TKI Osimertinib.

        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.

        Exclusion Criteria:

          -  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.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate(ORR) according to resist 1.1
Time Frame:2years
Safety Issue:
Description:To evaluate the response to therapy and Objective Response Rate of the combination of Osimertinib and Aspirin in patients who has metastatic pulmonary adenocarcinoma disease progression to 3st generation EGFR-TKI Osimertinib.

Secondary Outcome Measures

Measure:disease control rate(DCR) according to resist 1.1
Time Frame:2years
Safety Issue:
Description:To evaluate the response to therapy and disease control rate of the combination of Osimertinib and Aspirin in patients who has metastatic pulmonary adenocarcinoma disease progression to 3st generation EGFR-TKI Osimertinib.
Measure:Time to progression(TTP) according to resist 1.1
Time Frame:2years
Safety Issue:
Description:To evaluate the response to therapy and Time to progression of the combination of Osimertinib and Aspirin in patients who has metastatic pulmonary adenocarcinoma disease progression to 3st generation EGFR-TKI Osimertinib.
Measure:duration of Response(DOR) according to resist 1.1
Time Frame:2years
Safety Issue:
Description:To evaluate the response to therapy and duration of Response of the combination of Osimertinib and Aspirin in patients who has metastatic pulmonary adenocarcinoma disease progression to 3st generation EGFR-TKI Osimertinib.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Daping Hospital and the Research Institute of Surgery of the Third Military Medical University

Trial Keywords

  • lung cancer
  • Aspirin
  • Osimertinib
  • EGFR-TKI
  • resistance

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