Erlotinib Hydrochloride or Crizotinib and Chemoradiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer

Study ID

Cancer Related

Healthy Volunteers

Study Sites

  • Clements University Hospital
  • UT Southwestern Ambulatory Services
  • Parkland Health & Hospital System

Irma Smith

Principal Investigator
Hak Choy, M.D.

Official Title

A Randomized Phase II Study of Individualized Combined Modality Therapy for Stage III Non-small Cell Lung Cancer (NSCLC)

Brief Overview

This randomized phase II trial studies how well erlotinib hydrochloride or crizotinib with
chemoradiation therapy works in treating patients with stage III non-small cell lung cancer.
Radiation therapy uses high energy x rays to kill tumor cells. Specialized radiation therapy
that delivers a high dose of radiation directly to the tumor may kill more tumor cells and
cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin,
etoposide, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor
cells, either by killing the cells, by stopping them from dividing, or by stopping them from
spreading. It is not yet known whether giving erlotinib hydrochloride is more effective than
crizotinib with chemoradiation therapy in treating patients with non-small cell lung cancer.



I. To assess whether patients with unresectable local-regionally advanced non-small cell
lung cancer (NSCLC) treated with targeted agents based on molecular characteristics have a
longer progression-free survival than those treated with standard care therapy alone.


I. To evaluate response rate. II. To assess toxicity. III. To assess overall survival. IV.
To correlate clinical outcomes with tumor molecular aberrations identified from deep
sequencing of selected kinomes in patients from whom adequate baseline tissue is available.

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

ARM I (induction therapy): Patients receive erlotinib hydrochloride orally (PO) once daily
(QD) for up to 12 weeks. Patients who have had no response (partial or complete) after 6
weeks undergo concurrent chemoradiation therapy immediately. After 2 weeks of completion of
induction therapy, patients receive chemoradiation.

ARM III (induction therapy): Patients receive crizotinib PO twice daily (BID) for up to 12
weeks. Patients who have had no response (partial or complete) after 6 weeks undergo
concurrent chemoradiation therapy immediately. After 2 weeks of completion of induction
therapy, patients receive chemoradiation.

ARMS II AND IV (concurrent chemoradiation): Patients receive concurrent chemotherapy with
thoracic radiation therapy beginning on day 1. Treatment continues in the absence of disease
progression or unacceptable toxicity.

CHEMORADIATION: In all treatment arms, patients undergo concurrent intensity modulated
radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3-D CRT) QD 5 days a
week for 6 weeks. Patients receive 1 of 2 chemotherapy regimens based on the discretion of
the treating physician. Patients receive cisplatin intravenously (IV) over 1-2 hours on days
1, 8, 29, and 36 and etoposide IV over 1 hour on days 1-5 and 29-33. Treatment repeats every
4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity.
Some patients receive paclitaxel IV and carboplatin IV on days 1, 8, 15, 22, 29, and 36
during radiation therapy for 6 weeks. Two courses of consolidation treatment will begin 4-6
weeks after completion of radiation therapy with paclitaxel IV on days 1 and 22 and
carboplatin IV on days 1 and 22 in the absence of disease progression or unacceptable

After completion of study treatment, patients are followed up at 1 month, every 3 months for
2 years, every 6 months for 3 years, and then annually for 5 years.

Participant Eligibility

Inclusion Criteria:

- Histologically or cytologically confirmed, newly diagnosed non-squamous NSCLC

- Unresectable stage IIIA or IIIB disease; patients must be surgically staged to
confirm N2 or N3 disease; patients may have invasive mediastinal staging by
mediastinoscopy, mediastinotomy, endobronchial ultrasound transbronchial aspiration
(EBUS-TBNA), endoscopic ultrasound (EUS), or video-assisted thoracoscopic surgery

- Patients with any tumor (T) with node (N)2 or N3 are eligible; patients with T3,
N1-N3 disease are eligible if deemed unresectable; patients with T4, any N are

- Patients must have measurable disease, i.e., lesions that can be accurately measured
in at least 1 dimension (longest dimension in the plane of measurement is to be
recorded) with a minimum size of 10 mm by computed tomography (CT) scan (CT scan
slice thickness no greater than 5 mm)

- Patients with a pleural effusion, which is a transudate, cytologically negative and
non-bloody, are eligible if the radiation oncologist feels the tumor can be
encompassed within a reasonable field of radiotherapy

- If a pleural effusion can be seen on the chest CT but not on chest x-ray and is too
small to tap, the patient will be eligible; patients who develop a new pleural
effusion after thoracotomy or other invasive thoracic procedure will be eligible

- The institution's pre-enrollment biomarker screening at a Clinical Laboratory
Improvement Amendments (CLIA) certified lab documents presence of known "sensitive"
mutations in epidermal growth factor receptor tyrosine kinase (EGFR TK) domain (exon
19 deletion, L858) and/or EML4-anaplastic lymphoma kinase (ALK) fusion arrangement;
either the primary tumor or the metastatic lymph node tissue may be used for testing
of mutations

- The institution's pre-enrollment biomarker screening at a CLIA certified lab
documents absence of T790M mutation in the EGFR TK domain

- Appropriate stage for protocol entry, including no distant metastases, based upon the
following minimum diagnostic workup:

- History/physical examination, including recording of pulse, blood pressure (BP),
weight, and body surface area, within 45 days prior to registration

- Whole body fludeoxyglucose-positron emission tomography (FDG-PET)/CT (orbits to
mid-thighs) within 30 days prior to registration; PET/CT must be negative for
distant metastasis

- CT scan with contrast of the chest and upper abdomen to include liver and
adrenals (unless medically contraindicated) within 30 days prior to registration

- Magnetic resonance imaging (MRI) of the brain with contrast (or CT scan with
contrast, if MRI medically contraindicated) within 30 days prior to registration

- Zubrod performance status 0-1 within 14 days prior to registration

- Absolute neutrophil count (ANC) >= 1,000 cells/mm^3

- Platelets >= 100,000 cells/mm^3

- Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve
hemoglobin [Hgb] >= 8.0 g/dl is acceptable)

- Serum creatinine < 1.5 mg/dL or calculated creatinine clearance >= 50 ml/min (by
Cockcroft-Gault formula) within 14 days prior to registration

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
of normal (ULN) within 14 days prior to registration

- Bilirubin within normal institutional limits within 14 days prior to registration

- Negative serum pregnancy test within 14 days prior to registration for women of
childbearing potential

- Patient must provide study specific informed consent prior to study entry, including
consent for mandatory screening of tissue

Exclusion Criteria:

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 730 days (2 years) (for example, carcinoma in situ of the breast,
oral cavity, or cervix are all permissible)

- Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a
different cancer is allowable

- Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields

- Atelectasis of the entire lung

- Contralateral hilar node involvement

- Exudative, bloody, or cytologically malignant effusions

- Severe, active co-morbidity, defined as follows:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months

- Transmural myocardial infarction within the last 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at the
time of registration

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of
registration; hepatic insufficiency resulting in clinical jaundice and/or
coagulation defects

- Acquired immune deficiency syndrome (AIDS) based upon current Centers for
Disease Control and Prevention (CDC) definition; note, however, that human
immunodeficiency virus (HIV) testing is not required for entry into this
protocol; protocol-specific requirements may also exclude immuno-compromised

- Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception

- Prior allergic reaction to the study drug(s) involved in this protocol