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A Randomised Phase II Trial of Osimertinib With or Without SRS for EGFR Mutated NSCLC With Brain Metastases

NCT03497767

Description:

20-40% of patients with NSCLC will develop brain metastases at some point during their course of disease. Osimertinib has demonstrated intracranial activity in EFGR mutated NSCLC with leptomeningeal disease in the phase 1 BLOOM study. Stereotactic radiosurgery (SRS) is one of the standard local treatment for patients with limited number of brain metastases. Currently, it is unclear whether adding SRS to Osimertinib will result in superior intracranial disease control in patients with EGFR mutated NSCLC with brain metastases diagnosed de novo or developed while on first line EGFR tyrosine kinase inhibitors (TKIs) such as Erlotinib and Gefinitib. The aim of this study is to compare the effects of Osimertinib alone versus SRS plus Osimertinib on intra-cranial disease control in EGFR mutated NSCLC with brain metastases diagnosed or developed while on first line EGFR tyrosine kinase inhibitors.

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

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Randomised Phase II Trial of Osimertinib With or Without SRS for EGFR Mutated NSCLC With Brain Metastases
  • Official Title: A Randomised Phase II Trial of Osimertinib With or Without Stereotactic Radiosurgery for EGFR Mutated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: TROG 17.02
  • NCT ID: NCT03497767

Conditions

  • Metastatic Non Small Cell Lung Cancer

Interventions

DrugSynonymsArms
OsimertinibTagrissoOsimertinib

Purpose

20-40% of patients with NSCLC will develop brain metastases at some point during their course of disease. Osimertinib has demonstrated intracranial activity in EFGR mutated NSCLC with leptomeningeal disease in the phase 1 BLOOM study. Stereotactic radiosurgery (SRS) is one of the standard local treatment for patients with limited number of brain metastases. Currently, it is unclear whether adding SRS to Osimertinib will result in superior intracranial disease control in patients with EGFR mutated NSCLC with brain metastases diagnosed de novo or developed while on first line EGFR tyrosine kinase inhibitors (TKIs) such as Erlotinib and Gefinitib. The aim of this study is to compare the effects of Osimertinib alone versus SRS plus Osimertinib on intra-cranial disease control in EGFR mutated NSCLC with brain metastases diagnosed or developed while on first line EGFR tyrosine kinase inhibitors.

Trial Arms

NameTypeDescriptionInterventions
OsimertinibExperimental80mg Osimerinib taken once daily
  • Osimertinib
Stereotactic Radiosurgery + OsimertinibExperimentalUpfront Stereotactic Radiosurgery (SRS) followed by 80mg Osimerinib taken once daily
  • Osimertinib

Eligibility Criteria

        Inclusion Criteria:

          1. Provided written informed consent

          2. ≥ 18 years of age

          3. Histological or cytological documented NSCLC

          4. Metastatic NSCLC, not amenable to curative surgery or radiotherapy

          5. Brain metastases that meet the following criteria;

               1. Four or less lesions amenable to SRS

               2. Lesion/s visible and measurable on MRI

               3. Sum of lesion diameters ≤40mm

               4. Diagnosed de novo (i.e. at the same time with a new diagnosis of NSCLC) or
                  developed as a new site of progression while on first line EGFR TKI

             NOTE: Surgery as part of local practice for management of brain metastasis is allowed.
             Patients must still fulfil all other criteria, particularly criteria 5a, 5b, 5c and 5d
             pre-surgery, to be eligible for the study. Lesions that are partially or completely
             resected should not be used as a target lesion for MRI assessment.

          6. Documented EGFR mutation

          7. Karnofsky performance status 80-100 with no deterioration over the previous 2 weeks
             and a minimum life expectancy of 12 weeks

          8. Female patients who;

               1. are willing to use adequate contraceptive measures until 6 weeks after the final
                  dose of study treatment

               2. are not breast feeding

               3. have a negative pregnancy test prior to start of dosing if of child bearing
                  potential or have evidence of non-child bearing potential

          9. Male patients who are willing to use barrier contraception (i.e. condoms) until 4
             months after the final dose of study treatment

        Exclusion Criteria:

          1. Treatment with any of the following:

               1. Prior systemic therapy for patients with newly diagnosed metastatic NSCLC and
                  brain metastases de novo.

               2. More than one prior line of treatment for patients who developed brain metastases
                  while on first line EGFR TKI.

               3. An EGFR TKI (e.g. Erlotinib, Gefitinib or Afatinib) within 8 days or
                  approximately 5x half life, whichever is the longer, of the first dose of study
                  treatment.

               4. Previous treatment with Osimertinib or a 3rd generation EGFR TKI.

               5. Previous treatment with checkpoint inhibitors immunotherapy.

               6. Major surgery (excluding placement of vascular access) within 4 weeks of
                  randomisation.

               7. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field
                  of radiation within 4 weeks of randomization.

               8. Medications or herbal supplements known to be potent inhibitors or inducers of
                  CYP3A4 and are unable to stop use within the recommended wash out period prior to
                  receiving the first dose of Osimertinib

               9. An investigational drug within five half-lives of the compound.

              10. Any other cytotoxic chemotherapy, investigational agents or other anticancer
                  drugs from a previous treatment regimen or clinical study within 14 days of
                  randomisation.

          2. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 (with the
             exception of alopecia grade 2) at the time of starting study treatment.

          3. Spinal cord compression unless asymptomatic and stable.

          4. Leptomeningeal disease.

          5. Prior history of brain metastases with previous treatment that would preclude SRS.
             These patients will include those where tumour assessments as per RANO-criteria are
             not possible

          6. Moderate or severe symptomatic brain metastases defined as per Radiation Therapy
             Oncology Group acute morbidity grade 3 to 4.

          7. Brain metastases in the brainstem.

          8. 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 jeopardize
             compliance with the protocol, or active infection including hepatitis B, hepatitis C
             and human immunodeficiency virus (HIV). Screening for chronic conditions is not
             required.

          9. 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.

         10. Any of the following cardiac criteria:

               1. Mean resting corrected QT interval (QTc) > 470 msec, obtained from 3
                  electrocardiograms (ECGs).

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

               3. 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.

         11. Past medical history of Interstitial Lung Disease (ILD), drug-induced ILD, radiation
             pneumonitis which required steroid treatment, or any evidence of clinically active
             interstitial lung disease.

         12. Inadequate bone marrow reserve or organ function

         13. History of hypersensitivity of drugs with a similar chemical structure or class to
             Osimertinib or any excipients of these agents.

         14. Involvement in the planning and conduct of the study

         15. Judgement 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Intracranial progression free survival at 12 months
Time Frame:12 months post randomisation
Safety Issue:
Description:To assess the efficacy of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib by assessment of intracranial progression free survival at 12 months.

Secondary Outcome Measures

Measure:Use of salvage whole-brain radiotherapy (WBRT)
Time Frame:18 months post randomisation
Safety Issue:
Description:To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on use of salvage whole-brain radiotherapy (WBRT) +/- neurosurgery.
Measure:Local brain failure
Time Frame:18 months post randomisation
Safety Issue:
Description:To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on local brain failure.
Measure:Distant brain failure
Time Frame:18 months post randomisation
Safety Issue:
Description:To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on distant brain failure.
Measure:Extra-cranial progression
Time Frame:18 months post randomisation
Safety Issue:
Description:To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on extra-cranial progression.
Measure:Overall Survival
Time Frame:18 months post randomisation
Safety Issue:
Description:To further assess the efficacy of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib in terms of overall survival.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Trans-Tasman Radiation Oncology Group (TROG)

Trial Keywords

  • Non Small Cell Lung Cancer (NSCLC)
  • EGFR mutation
  • Osimertinib
  • Stereotactic Radiosurgery

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