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Pilot Neoadjuvant Study of ZD1839 (IRESSA®) as Single Agent Preoperative Therapy for Clinical Stage 1A and 1B (T1-2N0), II (T1-2N1, T3N0) and Selected IIIA (T3N1) Non-Small Cell Lung Cancer (NSCLC) With Molecular Correlates

18 Years
Not Enrolling
Lung Cancer

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Trial Information

Pilot Neoadjuvant Study of ZD1839 (IRESSA®) as Single Agent Preoperative Therapy for Clinical Stage 1A and 1B (T1-2N0), II (T1-2N1, T3N0) and Selected IIIA (T3N1) Non-Small Cell Lung Cancer (NSCLC) With Molecular Correlates



- Determine the effects of neoadjuvant gefitinib on downstream signaling pathways,
including Src-Stat3, PI3K/Akt, ERK activity, and Bcl-2 family members in patients with
resectable stage I-IIIA non-small cell lung cancer.

- Determine the effects of this drug on cell cycle and apoptosis within the primary
tumor, by measuring changes in pre- and post-treatment Ki-67, Mcm2, cleaved caspase-3,
and ApoTag, in these patients.


- Determine the clinical response rate in patients treated with this drug.

- Determine the pathological response rate, defined as > 95% necrosis or fibrosis in the
pathological specimen, in patients treated with this drug.

- Determine the metabolic activity of this drug in these patients.

- Determine the safety, tolerability, and feasibility of this drug, in terms of toxicity
and post-treatment resectability, in these patients.

- Correlate plasma and tumor concentrations of this drug with changes in post-treatment
molecular markers in these patients.

- Identify a gene profile that predicts response to this drug in these patients.

OUTLINE: This is an open-label, pilot study.

Patients receive oral gefitinib once daily for 4 weeks in the absence of disease progression
or unacceptable toxicity.

Within 3 days after completion of gefitinib, patients undergo restaging evaluation. Patients
whose disease is still considered resectable proceed to surgery. Patients undergo
thoracotomy with lobectomy or pneumonectomy OR sleeve resection. Patients also undergo
mediastinal lymph node dissection. After surgical resection, treatment with gefitinib may
continue off study at the discretion of the principal investigator.

After completion of study therapy, patients are followed at 30 days, every 4 months for 1
year, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study within 12.5 months.

Inclusion Criteria


- Histologically confirmed resectable non-small cell lung cancer (NSCLC), meeting 1 of
the following clinical staging criteria:

- Stage IA or IB (T1-2, N0)

- Stage II (T1-2, N1 with negative mediastinoscopy or T3, N0)

- Stage IIIA (T3, N1 with negative mediastinoscopy)

- Level 10 hilar nodes may be positive provided mediastinoscopy is negative

- The following are not allowed (as evidenced by clinical staging criteria [CT scan,
positron-emission tomography (PET) scan, or mediastinoscopy):

- Positive N2 lymph nodes (ipsilateral/subcarinal mediastinal lymph nodes)

- Positive N3 lymph nodes (contralateral mediastinal/hilar and
supraclavicular/scalene lymph nodes)

- T4 primary tumor (malignant pleural effusion or mediastinal invasion)

- Symptomatic tumors (T3, N0-1) involving the superior sulcus (i.e., Pancoast

- Measurable disease by contrast-enhanced CT scan

- No metastatic disease (except peribronchial or hilar lymph node involvement [N1]) by
fludeoxyglucose F 18 PET scan

- No malignant pleural effusion by preoperative evaluation

- Pleural effusions visible only on CT scan that are not large enough for safe
thoracentesis are allowed

- No exudative effusions (even if cytologically negative), as evidenced by any of
the following:

- Ratio of pleural fluid protein to serum protein > 0.5

- Ratio of pleural fluid lactic dehydrogenase (LDH) to serum LDH ≥ 0.6

- Pleural fluid LDH > 200 IU/L

- No superior vena cava syndrome

- No spinal cord compression



- 18 and over

Performance status

- Eastern Cooperative Oncology Group (ECOG) 0-1

Life expectancy

- Not specified


- WBC ≥ 4,000/mm^3

- Absolute granulocyte count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3


- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST or ALT ≤ 2 times ULN

- Alkaline phosphatase ≤ 2 times ULN


- Creatinine < 1.5 times ULN


- No uncontrolled ventricular arrhythmia

- No myocardial infarction within the past 3 months


- Pre-resection FEV_1 > 2.0 L OR

- Predicted post-resection FEV_1 > 1.0 L

- No clinically active interstitial lung disease

- Chronic stable asymptomatic radiographic changes allowed

- No post-obstructive pneumonia


- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Willing to provide tumor biopsy pre- and post-gefitinib administration AND undergo
PET scan

- No known severe hypersensitivity to study drug or any of its excipients

- No uncontrolled major seizure disorder

- No unstable or uncontrolled diabetes mellitus

- No serious infection requiring IV antibiotics

- No grade 3 neuropathy

- No other malignancy within the past 5 years except adequately treated basal cell or
squamous cell skin cancer or carcinoma in situ of the cervix

- No other unstable or serious medical condition that would preclude study treatment or

- No psychiatric disorder that would preclude giving informed consent

- No psychological, familial, sociological, or geographical condition that would
preclude study compliance and follow up

- No other significant clinical disorder or laboratory finding that would preclude
study participation


Biologic therapy

- Not specified


- No prior or concurrent systemic chemotherapy for NSCLC

Endocrine therapy

- Not specified


- No prior or concurrent radiotherapy for NSCLC


- Recovered from prior oncologic or other major surgery

- At least 5 years since prior resection of lung disease

- No prior surgery for NSCLC

- No concurrent ophthalmic surgery


- More than 30 days since prior non-approved or investigational drugs

- No other concurrent therapy for NSCLC

- No other concurrent investigational therapy

- No concurrent use of any of the following medications:

- Phenytoin

- Carbamazepine

- Barbiturates (e.g., phenobarbital)

- Rifampin

- Hypericum perforatum (St. John's wort)

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall Response Rate (ORR)

Outcome Description:

Objective Response Rate according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Investigators planned to use this pilot study of neoadjuvant ZD1839 in patients with resectable NSCLC to specifically correlate molecular parameters to the primary clinical study endpoint clinical response assessed by CT response and PET scan response of the primary tumor.

Outcome Time Frame:

3 years

Safety Issue:


Principal Investigator

Eric B. Haura, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

October 2004

Completion Date:

March 2009

Related Keywords:

  • Lung Cancer
  • stage II non-small cell lung cancer
  • stage IIIA non-small cell lung cancer
  • stage IA non-small cell lung cancer
  • stage IB non-small cell lung cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



H. Lee Moffitt Cancer Center and Research Institute Tampa, Florida  33612