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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03497767
Recruitment Status : Recruiting
First Posted : April 13, 2018
Last Update Posted : February 17, 2020
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
Actual Study Start Date : August 15, 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 21 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.



Information from the National Library of Medicine

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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. Has reached the age of majority in the country of treatment (i.e. ≥ 18 years in Australia; ≥ 21 years in Singapore)
  3. Histological or cytological documented NSCLC
  4. Metastatic NSCLC, not amenable to curative surgery or curative radiotherapy
  5. Brain metastases that meet the following criteria;

    1. ≤ 10 lesion/s visible and measurable on protocol screening MRI;

      • At least one brain metastases able to be treated with SRS
      • Definite but small brain metastases not for SRS treatment due to size, as per physician discretion, are included in the total
      • Equivocal small lesions are not included in the total
    2. No single brain metastasis exceeding 30mm longest diameter
    3. Total brain metastasis volume ≤ 15cc;

      - Total brain metastases volume on protocol screening MRI should be using the formula (4/3) x (3.14159265359) x (1/2 x size lesion in centimetre)3. Table 1: Brain metastases volume estimates provides an estimate of the volume of brain metastases based on the size of the lesion

    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 the management of brain metastasis is allowed but must be completed between 2 to 4 weeks prior to randomisation. Patients must still fulfil criteria 5a, 5b and 5d pre-surgery, and have at least one target lesion post-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;

    1. Patients who developed brain metastases as a site of disease progression while on first line EGFR TKIs must have T790M mutation.
    2. Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be sensitive to Osimertinib - These include exon 19 del; L858R (exon 21); G719X (exon 18); L861G (exon 21); S768I (exon 20) and T790M (exon 20) NOTE: Mutation analysis is to be done as per local practice. Please see section 7.1.1 for the recommended clinical practice for analysis.
  7. Karnofsky performance status 60-100 (ECOG performance status ≤2) 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 the start of dosing if of child bearing potential or have evidence of non-child bearing potential by fulfilling one of the following criteria at screening:

    i. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ii. Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) levels in the post-menopausal range for the institution iii. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation

  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.

      NOTE: Prior adjuvant chemotherapy or chemotherapy used as radio sensitisation followed by maintenance immunotherapy for non-resectable early stage NSCLC are allowed if such treatments were more than 6 months ago.

    2. Prior whole brain radiotherapy (WBRT)
    3. Radiologically progressive brain metastasis that underwent prior SRS (second line patients)
    4. Previous treatment with Osimertinib or a 3rd generation EGFR TKI. TROG 17.02 OUTRUN Protocol; Version 3.0, 02 July 2019 Page 23 of 74
    5. Previous treatment with checkpoint inhibitors immunotherapy for metastatic NSCLC.
    6. Major surgery within 4 weeks of randomisation (excluding placement of vascular access and surgery as part of local practice for the management of brain metastases, as outlined in inclusion criterion 5).
    7. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of randomisation.
    8. Medications or herbal supplements known to be potent inducers of CYP3A4 and are unable to stop use within the recommended wash out period prior to receiving the first dose of Osimertinib, see Table 7: Medications to avoid and withdrawal periods and Table 8 NOTE: All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4
    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. Moderate or severe symptomatic brain metastases defined as per Radiation Therapy Oncology Group acute morbidity grade 3 to 4.

    NOTE:

    • Grade 3 refers to neurological findings requiring hospitalisation for initial management.
    • Grade 4 refers to serious neurological impairment including paralysis, coma or seizures more than three times per week despite medication and requires hospitalization.
  6. Brain metastases in the brainstem.
  7. 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.
  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:

    1. Resting corrected QT interval (QTc) > 470 msec, obtained from an electrocardiogram (ECG).
    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.
  10. Patients with congenital long QT syndrome (CLQTS)
  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 as demonstrated by any of the following laboratory values:

    1. Absolute neutrophil count < 1.5 X 109/L TROG 17.02 OUTRUN Protocol; Version 3.0, 02 July 2019 Page 24 of 74
    2. Platelet count < 100 X 109/L
    3. Haemoglobin < 90 g/L
    4. Alanine aminotransferase (ALT) > 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases
    5. Aspartate aminotransferase (AST) > 2.5 times ULN if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases.
    6. Total bilirubin > 1.5 times ULN if no liver metastases or > 3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) or liver metastases.
    7. Creatinine > 1.5 times ULN concurrent with creatinine clearance < 50ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN.
  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, New South Wales
Calvary Mater Not yet recruiting
Newcastle, New South Wales, Australia, 2298
Contact: Jane Ludbrook         
Liverpool Hospital Recruiting
Sydney, New South Wales, Australia, 2002
Contact: Victoria Bray         
St. Vincents Hospital Not yet recruiting
Sydney, New South Wales, Australia, 2010
Contact: Cecilia Gzell         
Chris O'Brien Lifehouse Not yet recruiting
Sydney, New South Wales, Australia, 2050
Contact: Ee Siang Choong         
Westmead Hospital Recruiting
Sydney, New South Wales, Australia, 2145
Contact: Najmun Nahar         
Blacktown Hospital Recruiting
Sydney, New South Wales, Australia, 2148
Contact: Najmun Nahar         
St George Hospital Recruiting
Sydney, New South Wales, Australia, 2217
Principal Investigator: Chee Lee         
Australia, Queensland
Princess Alexandra Hospital Recruiting
Brisbane, Queensland, Australia, 4102
Contact: Angela Byron       pah-ctu-radonc@health.qld.gov.au   
Principal Investigator: Mark Pinkham         
ICON Cancer Centre Greenslopes Not yet recruiting
Brisbane, Queensland, Australia, 4120
Contact: Mark Pinkham         
Australia, Victoria
Peter MacCallum Cancer Center Recruiting
Melbourne, Victoria, Australia, 3002
Contact: Lisa Selbie       Lisa.Selbie@petermac.org   
Principal Investigator: Fiona Hegi-Johnson         
Monash Health Recruiting
Melbourne, Victoria, Australia, 3175
Contact: Karen Gillet         
Principal Investigator: Sagun Parakh         
Singapore
National University Hospital Not yet recruiting
Singapore, Singapore, 119074
Contact: Ivan Weng Keon Tham         
National Cancer Centre Not yet recruiting
Singapore, Singapore, 169610
Contact: Darren Lim         
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    
Other Study ID Numbers: TROG 17.02
First Posted: April 13, 2018    Key Record Dates
Last Update Posted: February 17, 2020
Last Verified: February 2020
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