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Osimertinib and Stereotactic Radiosurgery in Treating Patients with Brain Metastases from EGFR-Positive Non-Small-Cell Lung Cancer

Trial Status: Closed to Accrual

This phase I trial studies the side effects, best dose, and how well osimertinib works when used in combination with stereotactic radiosurgery in treating patients with EGFR-positive non-small cell lung cancer that has spread to the brain (brain metastases). Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Stereotactic radiosurgery is a specialized radiation therapy that delivers a single, high dose of radiation directly to the tumor and may cause less damage to normal tissue. Giving osimertinib with stereotactic radiosurgery may work better in treating patients with brain metastases from EGFR-positive non-small cell lung cancer.

Inclusion Criteria

  • Histologically confirmed EGFR mutation-positive NSCLC with newly diagnosed brain metastases.
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, 2.
  • Patients with 1-10 brain metastases will be candidates for osimertinib and SRS at the discretion of the treating radiation oncologist. Intra-cranial brain metastasis must measure 3 cm or less in the greatest dimension. Total volume of brain metastases cannot exceed 35 cc.
  • Being willing and able to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.
  • Life expectancy at least 12 weeks.
  • Any number of prior systemic therapies will be allowed, except osimertinib.
  • Hemoglobin >= 9 g/dL.
  • White blood count >= 3.0 x 10^9.
  • L granulocyte count >= 1.5 x 10^9/L.
  • Platelet count >= 100 x 10^9/L.
  • Serum bilirubin =< 1.5 x upper limit of normal (ULN).
  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 2 ULN (=< 5 x ULN when clearly attributable to the presence of liver metastases).
  • Serum creatinine =< 1.5 ULN or calculated creatinine clearance > 60 ml/min.
  • Ability to comply with study procedures and monitoring.
  • For women of childbearing potential, a negative pregnancy test should be obtained within one week prior to the start of therapy.
  • Male or female patients of reproductive potential need to employ two highly effective and acceptable forms of contraception throughout their participation in the study and for 120 days after last dose of osimertinib. Highly effective and acceptable forms of contraception are * Male condom plus spermicide * Cap plus spermicide * Diaphragm plus spermicide * Copper T * Progesterone T * Levonorgestrel-releasing intrauterine system (e.g., Mirena) * Implants * Hormone shot or injection * Combined pill * Minipill * Patch Postmenopausal woman on the study (that will not need contraception) is defined as: * Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments * Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the postmenopausal range for women under 50 * Radiation-induced oophorectomy with last menses > I year ago * Chemotherapy-induced menopause with > I year interval since last menses * Or surgical sterilization (bilateral oophorectomy or hysterectomy).

Exclusion Criteria

  • Patients with leptomeningeal metastases documented by magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) evaluation.
  • Evidence of intratumoral or peritumoral hemorrhage deemed significant by the treating physician.
  • Brain metastases within 5 mm of the optic chiasm or optic nerve.
  • Metastases in the brainstem (midbrain, pons, or medulla).
  • Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom, e.g., Crohn's disease, mal-absorption, or Common Terminology Criteria for Adverse Events (CTCAE) grade > 2 diarrhea of any etiology at baseline.
  • History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, New York Heart Association (NYHA) functional classification of 3 or 4.
  • Patients with known pre-existing interstitial lung disease (ILD), pneumonitis.
  • Unable to undergo brain MRI.
  • Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C.
  • All toxicities from prior therapies must have resolved to CTCAE v 4.0 grade 1 or better by the time of study enrollment.
  • Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes, second active malignancy) that could cause unacceptable safety risks or compromise compliance with the protocol.
  • Currently receiving other investigational cancer therapy.
  • Mean QT interval corrected heart rate (QTc) >= 470 ms calculated from 3 electrocardiograms using Fridericia's correction.
  • Left ventricular ejection fraction (LVEF) < 50%.
  • Concomitant use of strong CYP3A inhibitors including macrolide antibiotics (e.g. telithromycin), antifungals (e.g. itraconazole), antivirals (e.g. ritonavir), and nefazodone.
  • Concomitant use of strong CYP3A4 inducers (e.g. phenytoin, rifampicin, carbamazepine, St. John's wort).
  • Concomitant use of potent CYP2C8 inhibitors.
  • History of hypersensitivity to osimertinib or any of its excipients.
  • History and/or confirmed corneal ulceration.
  • Pregnant or breast feeding.


Miami Cancer Institute
Contact: Rupesh Rajesh Kotecha


Case Comprehensive Cancer Center
Contact: Glen H. J. Stevens
Phone: 216-445-1787


University of Virginia Cancer Center
Contact: Camilo Enrique Fadul
Phone: 434-243-7034


I. To determine the safety, tolerability and maximum tolerated dose (MTD) of osimertinib, when

administered in combination with stereotactic radiosurgery (SRS) in patients with EGFR positive non-small cell lung cancer (NSCLC) with brain metastases.


I. 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.

II. To assess the overall survival (OS) in patients with EGFR positive NSCLC brain metastases treated with osimertinib and SRS.

III. To compare results of our clinical trial to patients with EGFR positive NSCLC with brain metastases treated with SRS alone (1-10 brain Metastases).

IV. 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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by the investigator.


I. To assess the neurocognitive outcomes.

OUTLINE: This is a dose de-escalation study of osimertinib.

Patients receive osimertinib orally (PO) once daily (QD) starting on day 0 in the absence of disease progression or unacceptable toxicity. Patients undergo stereotactic radiosurgery of the brain over 30 minutes to 3 hours on day 8 per the treating physician.

After completion of study treatment, patients are followed for 30 days and then every 3 months for 3 years.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Case Comprehensive Cancer Center

Principal Investigator
Glen H. J. Stevens

  • Primary ID CASE3517
  • Secondary IDs NCI-2018-02234
  • ID NCT03535363