Clinical Trials /

Study of Osimertinib in Patients With a Lung Cancer With Brain or Leptomeningeal Metastases With EGFR Mutation

NCT04233021

Description:

Treatment of non-small cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) mutation is mainly based on tyrosine kinase inhibitors (TKIs) targeting EGFR. 1st or 2nd generation inhibitors have been shown to be superior to chemotherapy in terms of Progression-Free Survival (PFS) when used as 1st line treatment. In case of progression at several metastatic sites, systemic treatment will be considered and will depend on the presence of the TKI resistance mutation, the T790M mutation. In the presence of the T790M mutation, osimertinib is superior to chemotherapy in terms of progression-free survival, while in the absence of the T790M mutation, platinum salt chemotherapy is recommended. In case of local progression, treatment of the site in progression by radiotherapy and/or surgery is considered. As these local treatments can cause long-term adverse effects, systemic treatments are increasingly being considered in this indication. Brain and leptomeningeal metastases are the most frequent isolated site of progression in EGFR mutated patients treated with TKI. The high frequency of isolated cerebral and leptomeningeal progression is a consequence of the lower diffusion of 1st and 2nd generation TKIs in the central nervous system (CNS). Osimertinib is a 3rd generation TKI that has the particularity of overcoming the T790M mutation and having greater brain penetration than 1st or 2nd generation TKIs, which could make it an attractive therapeutic option in the event of brain progression or leptomeningeal progression. However, its efficacy in patients with cerebral or leptomeningeal metastases is still poorly understood.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Osimertinib in Patients With a Lung Cancer With Brain or Leptomeningeal Metastases With EGFR Mutation
  • Official Title: A Phase II, Multi-centre Study, to Evaluate the Efficacy and Safety of Osimertinib Treatment for Patients With EGFR-mutated Non-small Cell Lung Cancer (NSCLC) With Brain or Leptomeningeal Metastases

Clinical Trial IDs

  • ORG STUDY ID: IFCT-1804
  • NCT ID: NCT04233021

Conditions

  • Non Small Cell Lung Cancer Metastatic
  • Leptomeningeal Metastasis
  • Brain Metastases
  • EGFR Activating Mutation

Interventions

DrugSynonymsArms
OsimertinibOsimertinib

Purpose

Treatment of non-small cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) mutation is mainly based on tyrosine kinase inhibitors (TKIs) targeting EGFR. 1st or 2nd generation inhibitors have been shown to be superior to chemotherapy in terms of Progression-Free Survival (PFS) when used as 1st line treatment. In case of progression at several metastatic sites, systemic treatment will be considered and will depend on the presence of the TKI resistance mutation, the T790M mutation. In the presence of the T790M mutation, osimertinib is superior to chemotherapy in terms of progression-free survival, while in the absence of the T790M mutation, platinum salt chemotherapy is recommended. In case of local progression, treatment of the site in progression by radiotherapy and/or surgery is considered. As these local treatments can cause long-term adverse effects, systemic treatments are increasingly being considered in this indication. Brain and leptomeningeal metastases are the most frequent isolated site of progression in EGFR mutated patients treated with TKI. The high frequency of isolated cerebral and leptomeningeal progression is a consequence of the lower diffusion of 1st and 2nd generation TKIs in the central nervous system (CNS). Osimertinib is a 3rd generation TKI that has the particularity of overcoming the T790M mutation and having greater brain penetration than 1st or 2nd generation TKIs, which could make it an attractive therapeutic option in the event of brain progression or leptomeningeal progression. However, its efficacy in patients with cerebral or leptomeningeal metastases is still poorly understood.

Trial Arms

NameTypeDescriptionInterventions
OsimertinibExperimentalOsimertinib 80 mg/d
  • Osimertinib

Eligibility Criteria

        Inclusion Criteria:

          1. Patient with NSCLC (histological or cytological diagnosis) stage IV (8th UICC TNM
             edition, 2017).

          2. Patients with brain and/or leptomeningeal metastases. For cohort 1, the diagnosis of
             leptomeningeal metastasis requires either 1) detection of cancer cell or EGFR mutation
             in the CSF, or 2) presence of both clinical and neuro-imaging findings typical of LM,
             according to EANO-ESMO criteria.

          3. Presence of an activating EGFR mutation. The following mutations are considered to be
             activating: L858R, exon 19 deletions, exon 19 insertions, L861Q, G719X. The inclusion
             of patients with other mutations should be discussed on a case-by-case basis with
             IFCT.

             The presence of co-mutations on an oncogenic driver should be discussed with the IFCT
             before inclusion of the patient.

          4. Testing for T790M mutation in circulating tumour DNA or tumour tissue sample at
             progression on the last treatment received before inclusion.

          5. Maximum lines of anti-cancer treatment received before inclusion:

               -  For Cohort 1, patients could have been previously treated with maximum 3 lines of
                  anti-cancer treatment.

               -  For cohort 2, patients could have been previously treated with maximum 1 line of
                  anti-cancer treatment.

               -  For cohorts 3 and 4, patients could have been previously treated with maximum 2
                  lines of anti-cancer treatment. The line just before enrolment must be an EGFR
                  TKI.

             In case of previous chemotherapy, a wash-out period of 28 days will be applied. If
             there was any prior therapy with an investigational agent, a washout period of five
             half-lives of the compound or 3 months, whichever is greater, is needed.

          6. Patient having recovered from all grade ≤ 1 toxicities related to previous anticancer
             therapies (CTCAE v 5.0) except for alopecia, platinum-therapy-related neuropathy
             (where ≤2 is allowed).

          7. For cohorts 3 and 4, documented tumour progression after previous therapy according to
             RECIST 1.1 :

               -  Cohort 3: patients must have progressive brain metastases but no extra-CNS
                  progression.

               -  Cohort 4: patients must have progressive brain metastases and extra-CNS
                  progression.

          8. Presence of at least one evaluable lesion not previously irradiated according to
             RECIST 1.1. For cohort 2, 3 and 4, presence of one CNS evaluable lesion not previously
             irradiated according to RECIST 1.1.

          9. Age of at least 18 years old.

         10. Performance status (PS) 0 to 2 (ECOG) except for patients with leptomeningeal
             carcinomatosis (cohort 1) a PS 3 is authorised.

         11. Patient with a life expectancy of ≥ 6 weeks for cohort 1 and ≥ 12 weeks for cohort 2,
             3 and 4.

         12. Haematological function:

               -  Absolute number of neutrophils ≥ 1.5 x 109/L;

               -  Platelets ≥ 100 x 109/L;

               -  Haemoglobin ≥ 9 g/dL (transfusions to maintain or exceed this value are
                  accepted).

         13. Hepatic function:

               -  Total bilirubin ≤ 1.5 x UNL (Upper Normal Limit) or ≤ 3 x UNL in case of
                  documented Gilbert's syndrome or liver metastases;

               -  AST / ALT < 2.5 x UNL if no liver metastases or < 5 x UNL in case of liver
                  metastases.

         14. Renal function: Creatinine ≤1.5 x UNL. If creatinine > 1.5 x UNL, Creatinine clearance
             must be ≥ 50 mL/min (Cockroft or MDRD or CKD-epi)

         15. Coagulation:

               -  International Normalized Ratio (INR) ≤ 1.5 ;

               -  Prothrombin Ratio (PR) ≤ 1.5 x UNL.

         16. Patient having signed an informed consent form prior to any study specific procedure

         17. Patient able, according to the investigator, to comply with study requirements,

         18. Patient covered by a national health insurance

         19. Female subjects should be using highly effective contraceptive measures during the
             study and 2 months after discontinuing osimertinib (highly effective methods of
             contraception have a failure rate of < 1% when used consistently and correctly), 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

         20. Male subjects should be willing to use barrier contraception during the study and for
             4 months after discontinuing osimertinib

        Exclusion Criteria:

          1. Small cell lung cancer histology (SCLC) or tumours with mixt histology including a
             SCLC component.

          2. Previous treatment with osimertinib or another 3rd generation EGFR inhibitor.

          3. Previous treatment with any EGFR TKI (cohort 2 only)

          4. Brain progression requiring whole brain radiation without delay.

          5. Local treatments (neurosurgical or stereotactic treatment) for brain metastases
             performed less than 2 weeks prior to enrolment.

          6. Local brain treatment scheduled during study treatment.

          7. Patient who received radiotherapy including the lung fields ≤ 4 weeks before enrolment
             or patient who has not recovered from radiotherapy-induced toxicities. For all other
             body sites (including radiotherapy on thoracic vertebrae and ribs), radiotherapy ≤ 2
             weeks before enrolment or who have not recovered from radiotherapy-induced toxicities.
             Palliative radiotherapy for bone lesions ≤ 2 weeks before enrolment is authorised.

          8. Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (QTc) > 470 msec 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, electrolyte abnormalities (including: Serum/plasma
                  potassium < LLN; Serum/plasma magnesium < LLN; Serum/plasma calcium < LLN),
                  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.

          9. Active malignant disease other than NSCLC.

         10. Previous or active cancer within the previous 3 years (except for treated carcinoma in
             situ of the cervix or basal cell skin cancer).

         11. Others on-going anti-cancer treatment (including hormone therapy).

         12. Major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic) during the 4
             weeks before enrolment or patient who has not recovered from the side effects of such
             as procedure.

         13. Current severe infectious disease or fever > 38.5°C or evidence of any other
             pathology, degradation of organic or neurological functions, result of the physical
             examination or laboratory tests leading to suspect disease or a condition
             contra-indicating the use of the study treatment, which can impair the patient's
             compliance to the protocol conditions or expose to any possible risk of complications
             related to treatment.

         14. Clinically significant heart disease (e.g. active): stroke or myocardial infarction in
             the 6 months prior to inclusion, unstable angina, congestive heart failure grade > II
             according to New York Heart Association (NYHA) parameters, or cardiac arrhythmia
             requiring specific treatment during the study which could interfere with study
             compliance or which is not controlled by a treatment.

         15. 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).

         16. 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

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

         18. Currently receiving (or unable to stop use at least 3 week prior to receiving the
             first dose of study treatment) medications or herbal supplements known to be strong
             inducers of CYP3A4 (see Appendix 2). All patients must try to avoid concomitant use of
             any medications, herbal supplements and/or ingestion of foods with known inducer
             effects on CYP3A4.

         19. 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.

         20. Patient who is subject to legal protection or who is unable to express his will.

         21. Patient with a deficiency preventing complete understanding of the study requirements.

         22. Patient having already been included and treated in this study or in another clinical
             trial (except for biological trials consisting of taking samples only).

         23. Involvement in the planning and/or conduct of the study (applies to both Investigator
             staff and/or staff at the study site).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate
Time Frame:6 months
Safety Issue:
Description:Objective Response Rate at 6 months using EANO-ESMO criteria (cohort 1) and RECIST1.1 criteria (cohorts 2, 3, 4)

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:About 24 months
Safety Issue:
Description:Time from enrollment until death due to any cause
Measure:Progression-free survival
Time Frame:About 24 months
Safety Issue:
Description:Time from enrollment to first observation of progression (EANO-ESMO criteria (cohort 1) and RECIST1.1 criteria (cohorts 2, 3, 4)) or date of death (from any cause)
Measure:Incidence, type and severity of adverse event
Time Frame:From time of informed consent through treatment period and up to 30 days post last dose of study treatment (about 24 months)
Safety Issue:
Description:Descriptive statistics of safety will be presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
Measure:Evaluate the Quality of life
Time Frame:From time of randomisation through treatment period (about 24 months)
Safety Issue:
Description:EORTC QLQ-C30-LC13 (Qualify of Life Questionnaire C30 and Lung Cancer 13) questionnaire
Measure:Evaluate the Quality of life
Time Frame:From time of randomisation through treatment period (about 24 months)
Safety Issue:
Description:QLQ BN20 (Brain Neoplasm N20) questionnaire

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Intergroupe Francophone de Cancerologie Thoracique

Trial Keywords

  • IFCT
  • NSCLC
  • EGFR

Last Updated

February 7, 2020