Osimertinib With Stereotactic Radiosurgery (SRS) in Brain Metastases From EGFR Positive NSCLC

Study Overview
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Brief Summary
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Investigating potential of controlling brain metastases in patients with EGFR positive NSCLC.

Detailed Description
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In patients with EGFR positive NSCLC with 1-10 brain metastases, we are investigating whether we can control the macro brain metastases with Stereotactic Radiosurgery (SRS) and control the micro metastases with targeted agent Osimertinib and avoid whole brain radiation that could potentially lead to significant cognitive decline.

Official Title
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Phase 1 Trial of Osimertinib With Stereotactic Radiosurgery (SRS) in Patients With Brain Metastases From EGFR Positive Non-Small-Cell Lung Cancer (NSCLC)

Conditions
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NSCLC, Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Osimertinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed pathology of EGFR mutation positive NSCLC with new brain metastases. Ability to care for self and ability to walk 50% of waking hours (ECOG Performance Status of 0-2) 1-10 brain metastases with intra-cranial brain metastasis must measure 3cm or less in the greatest dimension. Hemoglobin ≥9 g/dL, White Blood Count Absolute ≥3.0 x 10^9/L, Granulocyte count ≥1.5 x 10^9/L, and platelet count ≥100 x 10^9/L Serum Bilirubin ≤ 1.5 x upper limit of normal (ULN) AST and/or ALT ≤ 2 ULN (≤ 5 x ULN when clearly attributable to liver metastases) Serum creatinine ≤ 1.5 ULN or calculated creatinine clearance > 60ml/min For women of childbearing potential-Negative pregnancy test within one week prior to start of therapy. For all sexually active male and female patients of reproductive potential, employ two methods of highly effective and acceptable forms of contraception throughout the study and for 120 days following the final dose of osimertinib. Exclusion Criteria: Patients with leptomeningeal metastases documented by MRI or cerebrospinal fluid (CSF). Significant intratumoral or peritumoral hemorrhage Brain metastases within 5 mm of the optic chiasm or optic nerve Brainstem metastases Gastrointestinal disorders with diarrhea as a major symptom Clinically significant or uncontrolled cardiac disease (NYHA functional classification of 3 or 4) Pre-existing interstitial lung disease or pneumonitis Unable to undergo brain MRI HIV or Hepatitis B or C Prior treatments must be resolved to an asymptomatic state at time of enrollment Medical conditions that could cause safety risks Currently receiving investigational cancer therapy. Mean QT interval corrected heart rate (QTc)≥470ms calculated from 3 EKGs Left Ventricular Ejection Fraction (LVEF) ≤ 50% Use of strong CYP3A inhibitors Use of strong CYP3A4 inducers Use of potent CYP2C8 inhibitors Hypersensitivity to osimertinib or any of its ingredients corneal ulceration pregnant or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maximum Tolerated Dose of Osimertinib with standard of care<br>For patients with 1-10 brain metastases, begin daily Osimeritinib 0-7 days prior to stereotactic radiosurgery (SRS), provide daily Osimeritinib concurrently with radiotherapy, followed by maintenance Osimeritinib until disease progression, withdrawal, or unacceptable toxicity. Dose Level 1: 80mg daily. Dose Level -1: 40mg daily | Drug: Osimertinib<br>* Drug: Osimertinib 80mg or 40mg<br>* Other names: Tagrisso;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Osimertinib with (SRS) | To determine the safety, tolerability and maximum tolerated dose of Osimertinib, when administered in combination with SRS in patients with EGFR positive NSCLC with brain metastases. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with progression free survival | To assess the six-month intra-cranial and extra-cranial progression-free survival (PFS-6) in patients with EGFR positive NSCLC brain metastases treated with Osimertinib and SRS (PFS is defined as the time from clinical registration to intra-or extra-cranial tumor progression or death) | 6 months | 
| Length of overall survival | To assess the overall survival (OS) in patients with EGFR positive NSCLC Brain Metastases treated with Osimertinib and SRS | 2 years | 
| Difference in outcome vs. standard of care | To compare results of our clinical trial to patients with EGFR positive NSCLC with brain metastases treated with SRS alone (1-10 brain Metastases) | 2 years | 
| Intra-cranial and Extra-cranial Overall Response Rate (ORR) | To assess Overall response rate (ORR) both intracranial and extracranial, defined as the proportion of patients with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by the investigator. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osimertinib