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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
4/12/2019

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

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
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)
NSW,QLD,VIC
Recruitment hospital [1] 0 0
Calvary Mater - Newcastle
Recruitment hospital [2] 0 0
Liverpool Hospital - Sydney
Recruitment hospital [3] 0 0
St. Vincents Hospital - Sydney
Recruitment hospital [4] 0 0
Chris O'Brien Lifehouse - Sydney
Recruitment hospital [5] 0 0
Westmead Hospital - Sydney
Recruitment hospital [6] 0 0
Blacktown Hospital - Sydney
Recruitment hospital [7] 0 0
St George Hospital - Sydney
Recruitment hospital [8] 0 0
Princess Alexandra Hospital - Brisbane
Recruitment hospital [9] 0 0
ICON Cancer Centre Greenslopes - Brisbane
Recruitment hospital [10] 0 0
Peter MacCallum Cancer Center - Melbourne
Recruitment hospital [11] 0 0
Monash Health - Melbourne
Recruitment postcode(s) [1] 0 0
2298 - Newcastle
Recruitment postcode(s) [2] 0 0
2002 - Sydney
Recruitment postcode(s) [3] 0 0
2010 - Sydney
Recruitment postcode(s) [4] 0 0
2050 - Sydney
Recruitment postcode(s) [5] 0 0
2145 - Sydney
Recruitment postcode(s) [6] 0 0
2148 - Sydney
Recruitment postcode(s) [7] 0 0
2217 - Sydney
Recruitment postcode(s) [8] 0 0
4102 - Brisbane
Recruitment postcode(s) [9] 0 0
4120 - Brisbane
Recruitment postcode(s) [10] 0 0
3002 - Melbourne
Recruitment postcode(s) [11] 0 0
3175 - Melbourne
Recruitment outside Australia
Country [1] 0 0
Singapore
State/province [1] 0 0
Singapore

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