Clinical Trials /

Whole Genomic Landscape of Advanced EGFR-mutant NSCLC

NCT03969823

Description:

This is a phase 2 single-arm, non-randomized multicentre and tissue acquisition study to evaluate acquired resistance mechanisms, efficacy, and safety in advanced, EGFR tyrosine kinase inhibitor-naïve NSCLC patients with EGFR-activating mutations who receive a first-line osimertinib orally at a dose of 80mg once daily.

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

Recruiting

Phase:

N/A

Trial Eligibility

Document

Title

  • Brief Title: Whole Genomic Landscape of Advanced EGFR-mutant NSCLC
  • Official Title: Whole Genomic Landscape of EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer Treated With First-Line Osimertinib (WARRIOR)

Clinical Trial IDs

  • ORG STUDY ID: ESR-18-14174
  • NCT ID: NCT03969823

Conditions

  • Locally Advanced or Metastatic NSCLC

Interventions

DrugSynonymsArms
TagrissoOsimertinibOsimertinib

Purpose

This is a phase 2 single-arm, non-randomized multicentre and tissue acquisition study to evaluate acquired resistance mechanisms, efficacy, and safety in advanced, EGFR tyrosine kinase inhibitor-naïve NSCLC patients with EGFR-activating mutations who receive a first-line osimertinib orally at a dose of 80mg once daily.

Detailed Description

      This open-label, single-arm, non-randomized phase 2 exploratory study has been designed to
      evaluate the mechanisms of resistance to first-line osimertinib 80mg once daily in NSCLC
      patients with EGFR-activating mutation who were naïve to chemotherapy as well as EGFR TKIs.
      Acquired resistance to first-line osimertinib is mediated by heterogeneous mechanisms
      including MET amplification (15%), secondary EGFR mutation including C797S or S768I (7%),
      PIK3CA mutation (7%), CDK4/6 amplification (5%), KRAS mutation (3%), BRAF mutation (3%),
      CCND1-3 amplification (3%), CCNE1 amplification (2%), HER2 amplification (2%), and SPTBN1-ALK
      fusion (1%) using plasma genotyping of FLAURA study (N=91). Therefore, this study is
      necessary to evaluate resistance mechanisms of ≥1% to first-line osimertinib in NSCLC
      patients with EGFR-activating mutations using whole-genomic profiling of tumours at
      pre-treatment and progression which acquisitions are mandatory.
    

Trial Arms

NameTypeDescriptionInterventions
OsimertinibExperimentalOsimertinib at 80mg dose will be administered orally once daily.
  • Tagrisso

Eligibility Criteria

        Inclusion Criteria:

          1. Provision of informed consent prior to any study specific procedures

          2. Male or female must be > 19 years of age

          3. Female subjects should be using highly effective contraceptive measures, and must have
             a negative pregnancy test and not be breast-feeding prior to start of dosing if of
             child-bearing potential or must have evidence of non-child-bearing potential by
             fulfilling one of the following criteria at screening:

               -  Post-menopausal defined as aged more than 50 years and amenorrheic for at least
                  12 months following cessation of all exogenous hormonal treatments

               -  Women under 50 years old would be consider postmenopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and with LH and FSH levels in the post-menopausal range for the
                  institution

               -  Documentation of irreversible surgical sterilisation by hysterectomy, bilateral
                  oophorectomy or bilateral salpingectomy but not tubal ligation

          4. Male subjects should be willing to use barrier contraception (see Restrictions,
             Section 3.8)

          5. Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy
             with local confirmation of the presence of EGFR TKI-sensitizing mutation (EGFR exon 19
             deletion or L858R mutation), either alone or in combination with other EGFR mutations
             excluding EGFR exon 20 insertion mutation

          6. Mandatory provision of fresh tumor sample before osimertinib via a biopsy or surgical
             resection

          7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          8. Patients must have a life expectancy ≥ 12 weeks.

          9. At least one lesion, not previously irradiated, that can be accurately measured at
             baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short
             axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and
             which is suitable for accurate repeated measurements

         10. Provision of informed consent for whole-genome and whole-exome sequencings

        Exclusion Criteria:

          1. Involvement in the planning and/or conduct of the study

          2. Previous treatment with an EGFR TKI

          3. Treatment with an investigational drug within five half-lives or 3 months, whichever
             is greater of the compound

          4. Patients currently receiving (or unable to stop use prior to receiving the first dose
             of study treatment) medications or herbal supplements known to be strong inducers of
             CYP3A4 (at least 3 weeks prior). All patients must try to avoid concomitant use of any
             medications, herbal supplements and/or ingestion of foods with known inducer effects
             on CYP3A4

          5. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of
             starting study treatment, with the exception of alopecia and grade 2, prior
             platinum-therapy-related neuropathy

          6. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled
             hypertension and active bleeding diatheses, which in the investigator's opinion makes
             it undesirable for the patient to participate in the trial or which would jeopardise
             compliance with the protocol, or active infection including hepatitis B, hepatitis C
             and human immunodeficiency virus (HIV). Screening for chronic conditions is not
             required

          7. Patients with spinal cord compression, symptomatic or unstable brain metastases except
             for those patients who have completed definitive therapy and have had a stable
             neurological status for at least 2 weeks after completion of definitive therapy.
             Patients who may be on corticosteroids to control brain metastases if they have been
             on a stable dose for 2 weeks (14 days) prior to the start of study treatment and are
             clinically asymptomatic are eligible

          8. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
             swallow the formulated product or previous significant bowel resection that would
             preclude adequate absorption of osimertinib

          9. Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (QTc) > 470 msec obtained from 3
                  electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc
                  value

               -  Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting ECG e.g. complete left bundle branch block, third degree heart block and
                  second degree heart block.

               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as heart failure, hypokalaemia, congenital long QT syndrome, family
                  history of long QT syndrome or unexplained sudden death under 40 years of age in
                  first degree relatives or any concomitant medication known to prolong the QT
                  interval and cause Torsades de Pointes.

         10. Past medical history of interstitial lung disease, drug-induced interstitial lung
             disease, radiation pneumonitis which required steroid treatment, or any evidence of
             clinically active interstitial lung disease

         11. Inadequate bone marrow reserve or organ function (as demonstrated by any of the
             following laboratory values: absolute neutrophil count <1.5 x 109/L; platelet count
             <100 x 109/L; haemoglobin <90 g/L; alanine aminotransferase >2.5 times ULN if no
             demonstrable liver metastases or >5 times ULN in the presence of liver metastases;
             aspartate aminotransferase >2.5 times ULN if no demonstrable liver metastases or >5
             times ULN in the presence of liver metastases; total bilirubin >1.5 times ULN if no
             liver metastases or >3 times ULN in the presence of documented Gilbert's Syndrome
             [unconjugated hyperbilirubinaemia] or liver metastases; serum creatinine >1.5 times
             ULN concurrent with creatinine clearance <50 mL/min [measured or calculated by
             Cockcroft and Gault equation]—confirmation of creatinine clearance is only required
             when creatinine is >1.5 times ULN

         12. History of hypersensitivity to any of the active or inactive excipients of osimertinib
             or drugs with a similar chemical structure or class to osimertinib

         13. Patients who are pregnant or breast-feeding

         14. Judgment by the investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and requirements

         15. Previous allogeneic bone marrow transplant

         16. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the
             genetic sample collection
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of acquired resistance mechanisms to osimertinib at disease progression
Time Frame:Through study completion, an average of 2 years
Safety Issue:
Description:Disease progression as defined by investigator assessments according to RECIST1.1

Secondary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Time Frame:Through study completion, an average of 2 years
Safety Issue:
Description:AEs/SAEs as defined by NCI CTCAE version 5.0
Measure:Progression-Free Survival (PFS)
Time Frame:Through study completion, an average of 2 years
Safety Issue:
Description:PFS as defined as the time from the date of initiation until the date of first documented progression
Measure:Overall Survival (OS)
Time Frame:Through study completion, an average of 2 years
Safety Issue:
Description:OS as defined as the time from the date of first dose until death due to any cause
Measure:Objective Response Rate (ORR)
Time Frame:Through study completion, an average of 2 years
Safety Issue:
Description:ORR using investigator assessments according RECIST1.1

Details

Phase:N/A
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Seoul National University Hospital

Trial Keywords

  • NSCLC
  • Osimertinib
  • EGFR exon 19 deletion or L858R mutation

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