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

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ClinicalTrials.gov Identifier: NCT03497767
Recruitment Status : Not yet recruiting
First Posted : April 13, 2018
Last Update Posted : February 19, 2019
Sponsor:
Information provided by (Responsible Party):
Trans-Tasman Radiation Oncology Group (TROG)

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Metastatic Non Small Cell Lung Cancer Drug: Osimertinib Radiation: Stereotactic Radiosurgery (SRS) Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : March 2019
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : March 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Osimertinib

Arm Intervention/treatment
Experimental: Osimertinib
80mg Osimerinib taken once daily
Drug: Osimertinib
All participants will receive a dose of Osimertinib 80mg once daily
Other Name: Tagrisso

Experimental: Stereotactic Radiosurgery + Osimertinib
Upfront Stereotactic Radiosurgery (SRS) followed by 80mg Osimerinib taken once daily
Drug: Osimertinib
All participants will receive a dose of Osimertinib 80mg once daily
Other Name: Tagrisso

Radiation: Stereotactic Radiosurgery (SRS)
Dose and fractionation depend on lesion size. All SRS must be completed within 14 days of randomisation and all lesions are to be treated within 7 days.




Primary Outcome Measures :
  1. Intracranial progression free survival at 12 months [ Time Frame: 12 months post randomisation ]
    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 :
  1. Use of salvage whole-brain radiotherapy (WBRT) [ Time Frame: 18 months post randomisation ]
    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.

  2. Local brain failure [ Time Frame: 18 months post randomisation ]
    To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on local brain failure.

  3. Distant brain failure [ Time Frame: 18 months post randomisation ]
    To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on distant brain failure.

  4. Extra-cranial progression [ Time Frame: 18 months post randomisation ]
    To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on extra-cranial progression.

  5. Overall Survival [ Time Frame: 18 months post randomisation ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03497767


Contacts
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Contact: Trial Coordinator +61 2 401 43911 OUTRUN@trog.com.au

Locations
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Australia, Victoria
Peter MacCallum Cancer Center Recruiting
Melbourne, Victoria, Australia, 3002
Contact: Lisa Selbie       Lisa.Selbie@petermac.org   
Principal Investigator: Fiona Hegi-Johnson         
Sponsors and Collaborators
Trans-Tasman Radiation Oncology Group (TROG)
Investigators
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Study Chair: Fiona Hegi-Johnson, Dr Peter MacCallum Cancer Centre, Australia
Study Chair: Chee Lee, Dr National Health and Medical Research Council, Australia
Study Chair: Ivan Tham, Dr National University Hospital, Singapore
Study Chair: Yu Yang Soon, Dr National University Hospital, Singapore

Additional Information:
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Responsible Party: Trans-Tasman Radiation Oncology Group (TROG)
ClinicalTrials.gov Identifier: NCT03497767     History of Changes
Other Study ID Numbers: TROG 17.02
First Posted: April 13, 2018    Key Record Dates
Last Update Posted: February 19, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Trans-Tasman Radiation Oncology Group (TROG):
Non Small Cell Lung Cancer (NSCLC)
EGFR mutation
Osimertinib
Stereotactic Radiosurgery
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Osimertinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action