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A Phase I Open-Label, Dose-Finding Study to Evaluate the Safety and Efficacy of Concurrent Radiosurgery and Erlotinib Administration in Non-Small Cell Lung Cancer Patients With Brain Metastases

Phase 1
18 Years
Not Enrolling
Lung Cancer, Metastatic Cancer

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Trial Information

A Phase I Open-Label, Dose-Finding Study to Evaluate the Safety and Efficacy of Concurrent Radiosurgery and Erlotinib Administration in Non-Small Cell Lung Cancer Patients With Brain Metastases



- To determine the acute as well as long-term toxicity (especially grade III
neurotoxicity) of concurrent erlotinib hydrochloride and single-fraction radiosurgery
in patients with non-small cell lung cancer (NSCLC) and brain metastases.


- To determine the freedom from progression in all detected lesions (i.e.,
radiosurgically treated and untreated) and the rate of response of radiosurgically
treated lesions in patients receiving concurrent erlotinib hydrochloride and
radiosurgery as compared with historical controls treated with gamma knife radiosurgery
alone at UCSF.

- To measure the rate of freedom from any CNS progression in these patients at 1 year
post treatment.

- To assess cerebrospinal fluid (CSF) distribution of erlotinib hydrochloride by
measuring both erlotinib hydrochloride and its major metabolite, OSI-420, in plasma and
CSF at 4 or more days after initial erlotinib hydrochloride administration but before
radiosurgery, and again at 4 weeks after stereotactic radiosurgery (optional).

- To perform CSF and serum biomarker analysis for NSCLC using 2-dimensional liquid
chromatography or mass spectrometry (2D-LC/MS).

- To determine the incidence of subclinical leptomeningeal disease in patients assigned
to gamma-knife treatment and who do not exhibit signs or symptoms or carcinomatous

OUTLINE: Patients receive oral erlotinib hydrochloride once daily for at least 7 days.
Patients then undergo stereotactic radiosurgery on day 0. Beginning the day after
radiosurgery, patients receive erlotinib hydrochloride once daily for 4 weeks in the absence
of disease progression or unacceptable toxicity. After completion of study therapy, patients
may continue to receive erlotinib hydrochloride at the discretion of their oncologist.

Patients undergo cerebrospinal fluid (CSF) and blood sample collection at baseline (at least
4 days after starting erlotinib hydrochloride and prior to radiosurgery) for pharmacokinetic
and biomarker correlative studies. Samples are analyzed for concentrations of erlotinib
hydrochloride by 2-dimensional-liquid chromatography/mass spectrometry and antithrombin by
enzyme-linked immunosorbent assay.

After completion of study therapy, patients are followed every 3 months for 1 year.

Inclusion Criteria


- Histologically confirmed non-small cell lung cancer (NSCLC) meeting the following

- Fewer than 5 intraparenchymal brain metastases by gadolinium-enhanced MRI
meeting the following criteria:

- Maximum diameter ≤ 4.0 cm

- If multiple lesions are present and one lesion is > 3.0 cm, the
remaining lesions must be ≤ 3.0 cm in maximum diameter

- No metastases within 3 mm of the optic nerve or optic chiasm such that some
portion of the optic nerve or chiasm would receive > 9 Gy from radiosurgery

- No metastases in the brainstem, midbrain, pons, or medulla

- No prior complete resection of a single brain metastasis or of all known brain

- Subtotal resection allowed provided residual disease is ≤ 4.0 cm in maximum

- No clinical or radiographic evidence of unstable systemic progression (other than the
study lesion[s]) within the past month

- Patients with brain metastases at initial presentation do not require 1 month of
scans documenting stable disease

- Isolated brain metastases with stable systemic disease allowed

- No leptomeningeal metastases by MRI and/or positive cerebrospinal fluid cytology


- Karnofsky performance status 60-100%

- Life expectancy ≥ 3 months

- ANC > 1,000/mm³

- Platelet count > 100,000/mm³

- Hemoglobin > 10 g/dL

- PT and PTT normal

- AST < 2 times upper limit of normal (ULN)

- Alkaline phosphatase < 2 times ULN

- Total bilirubin < 2 times ULN

- Lactic dehydrogenase < 2 times ULN

- Serum creatinine < 1.5 times ULN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 2 weeks after
completion of study therapy

- Neurologic function status 0-2

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to erlotinib hydrochloride

- No contraindication to MRI (e.g., cardiac pacemaker)

- No absolute contraindication to lumbar puncture


- See Disease Characteristics

- Prior systemic therapy allowed

- No prior cranial radiotherapy

- Prior radiotherapy to noncranial sites allowed

- More than 1 week since prior intrathecal chemotherapy or prior treatment of
leptomeningeal carcinoma

- No concurrent systemic therapy

- Prior or current erlotinib hydrochloride for treatment of systemic disease
allowed provided systemic disease has not progressed while on erlotinib

- No concurrent enzyme-inducing anticonvulsant

- If patients are on an enzyme-inducing anticonvulsant (e.g., phenytoin,
carbamazepine, or phenobarbital), the agent must be converted to a
nonenzyme-inducing anticonvulsant before or at the start of erlotinib
hydrochloride treatment

- No concurrent CYP3A4 inhibitors or inducers (e.g., Hypericum perforatum [St. John
wort] or ketoconazole)

- No other concurrent investigational therapy

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Acute and long-term toxicity (i.e., neurotoxicity, gastrointestinal, cutaneous, and hematologic) as assessed by NCI CTCAE v3.0.

Safety Issue:


Principal Investigator

James L. Rubenstein, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of California, San Francisco


United States: Food and Drug Administration

Study ID:




Start Date:

January 2009

Completion Date:

July 2009

Related Keywords:

  • Lung Cancer
  • Metastatic Cancer
  • stage IV non-small cell lung cancer
  • tumors metastatic to brain
  • recurrent non-small cell lung cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms
  • Neoplasm Metastasis
  • Neoplasms
  • Neoplasms, Second Primary



UCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California  94115