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

NCT03497767 | Completed Phase 2 DMC

• 1 other identifier: TROG 17.02
• Study Type: interventional
• Target: 40
• Locations: 2 countries
• Sites: 13

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.

Conditions

Metastatic Non Small Cell Lung Cancer

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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.

  12 months post randomisation

Secondary Outcomes (5)

• Use of salvage whole-brain radiotherapy (WBRT)

  18 months post randomisation

• Local brain failure

  18 months post randomisation

• Distant brain failure

  18 months post randomisation

• Extra-cranial progression

  18 months post randomisation

• Overall Survival

  18 months post randomisation

Study Arms (2)

Osimertinib

EXPERIMENTAL

80mg Osimerinib taken once daily

Drug: Osimertinib

Stereotactic Radiosurgery + Osimertinib

EXPERIMENTAL

Upfront Stereotactic Radiosurgery (SRS) followed by 80mg Osimerinib taken once daily

Drug: Osimertinib; Radiation: Stereotactic Radiosurgery (SRS)

Interventions

Osimertinib DRUG

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

Also known as: Tagrisso

Osimertinib; Stereotactic Radiosurgery + Osimertinib

Stereotactic Radiosurgery (SRS) RADIATION

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.

Stereotactic Radiosurgery + Osimertinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provided written informed consent
• Has reached the age of majority in the country of treatment (i.e. ≥ 18 years in Australia; ≥ 21 years in Singapore)
• Histological or cytological documented NSCLC
• Metastatic NSCLC, not amenable to curative surgery or curative radiotherapy
• Brain metastases that meet the following criteria;
• ≤ 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
• No single brain metastasis exceeding 30mm longest diameter
• 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
• 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.
• Documented EGFR mutation;

You may not qualify if:

• Treatment with any of the following:
• 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.
• Prior whole brain radiotherapy (WBRT)
• Radiologically progressive brain metastasis that underwent prior SRS (second line patients)
• Previous treatment with Osimertinib or a 3rd generation EGFR TKI.
• Previous treatment with checkpoint inhibitors immunotherapy for metastatic NSCLC.
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of randomisation.
• 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
• An investigational drug within five half-lives of the compound or 3 months, whichever is greater.
• Any other cytotoxic chemotherapy, investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days of randomisation.
• 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.
• Spinal cord compression unless asymptomatic and stable.
• Leptomeningeal disease.
• Moderate or severe symptomatic brain metastases defined as per Radiation Therapy Oncology Group acute morbidity grade 3 to 4.

Sponsors & Collaborators

• Trans Tasman Radiation Oncology Group: lead

Study Sites (13)

Calvary Mater

Newcastle, New South Wales, 2298, Australia

Location

Liverpool Hospital

Sydney, New South Wales, 2002, Australia

Location

St. Vincents Hospital

Sydney, New South Wales, 2010, Australia

Location

Westmead Hospital

Sydney, New South Wales, 2145, Australia

Location

Blacktown Hospital

Sydney, New South Wales, 2148, Australia

Location

St George Hospital

Sydney, New South Wales, 2217, Australia

Location

Princess Alexandra Hospital

Brisbane, Queensland, 4102, Australia

Location

ICON Cancer Centre Greenslopes

Brisbane, Queensland, 4120, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Location

Peter MacCallum Cancer Center

Melbourne, Victoria, 3002, Australia

Location

Monash Health

Melbourne, Victoria, 3175, Australia

Location

Sir Charles Gairdner

Perth, Western Australia, Australia

Location

National University Hospital

Singapore, 119074, Singapore

Location

Related Links

• Sponsor's webpage

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

osimertinib; Radiosurgery

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• 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

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2018
• First Posted: April 13, 2018
• Study Start: August 15, 2019
• Primary Completion: April 30, 2024
• Study Completion: April 30, 2024
• Last Updated: May 31, 2024

Record last verified: 2024-05

Locations

AU (12); SG (1)