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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03497767




Registration number
NCT03497767
Ethics application status
Date submitted
26/02/2018
Date registered
13/04/2018
Date last updated
19/02/2019

Titles & IDs
Public title
A Randomised Phase II Trial of Osimertinib With or Without SRS for EGFR Mutated NSCLC With Brain Metastases
Scientific 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
Secondary ID [1] 0 0
TROG 17.02
Universal Trial Number (UTN)
Trial acronym
OUTRUN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Non Small Cell Lung Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lung - Mesothelioma
Cancer 0 0 0 0
Lung - Non small cell
Cancer 0 0 0 0
Lung - Small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Osimertinib
Treatment: Other - Stereotactic Radiosurgery (SRS)

Experimental: Osimertinib - 80mg Osimerinib taken once daily

Experimental: Stereotactic Radiosurgery + Osimertinib - Upfront Stereotactic Radiosurgery (SRS) followed by 80mg Osimerinib taken once daily


Treatment: Drugs: Osimertinib
All participants will receive a dose of Osimertinib 80mg once daily

Treatment: Other: 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.

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Intracranial progression free survival at 12 months - 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.
Timepoint [1] 0 0
12 months post randomisation
Secondary outcome [1] 0 0
Use of salvage whole-brain radiotherapy (WBRT) - 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.
Timepoint [1] 0 0
18 months post randomisation
Secondary outcome [2] 0 0
Local brain failure - To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on local brain failure.
Timepoint [2] 0 0
18 months post randomisation
Secondary outcome [3] 0 0
Distant brain failure - To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on distant brain failure.
Timepoint [3] 0 0
18 months post randomisation
Secondary outcome [4] 0 0
Extra-cranial progression - To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on extra-cranial progression.
Timepoint [4] 0 0
18 months post randomisation
Secondary outcome [5] 0 0
Overall Survival - 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.
Timepoint [5] 0 0
18 months post randomisation

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Peter MacCallum Cancer Center - Melbourne
Recruitment postcode(s) [1] 0 0
3002 - Melbourne

Funding & Sponsors
Primary sponsor type
Other
Name
Trans-Tasman Radiation Oncology Group (TROG)
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT03497767
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Fiona Hegi-Johnson, Dr
Address 0 0
Peter MacCallum Cancer Centre, Australia
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Trial Coordinator
Address 0 0
Country 0 0
Phone 0 0
+61 2 401 43911
Fax 0 0
Email 0 0
OUTRUN@trog.com.au
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03497767