Neoadjuvant IRESSA As Single Agent PreopTherapy for NSCLC With Molecular Correlates

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

RATIONALE: Gefitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving gefitinib before surgery may shrink the tumor so it can be removed.

PURPOSE: This phase II trial is studying how well gefitinib works in treating patients who are undergoing surgery for stage I, stage II, or stage III non-small cell lung cancer.

Study Overview

• Status: Terminated
• Conditions: Lung Cancer
• Intervention / Treatment: Drug: ZD1839

Detailed Description

OBJECTIVES:

Primary

• 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.

Secondary

• 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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612-9497
      • H. Lee Moffitt Cancer Center and Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• 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 tumors)
• 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

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Eastern Cooperative Oncology Group (ECOG) 0-1

Life expectancy

• Not specified

Hematopoietic

• WBC ≥ 4,000/mm^3
• Absolute granulocyte count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST or ALT ≤ 2 times ULN
• Alkaline phosphatase ≤ 2 times ULN

Renal

• Creatinine < 1.5 times ULN

Cardiovascular

• No uncontrolled ventricular arrhythmia
• No myocardial infarction within the past 3 months

Pulmonary

• 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

Other

• 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 surgery
• 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

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior or concurrent systemic chemotherapy for NSCLC

Endocrine therapy

• Not specified

Radiotherapy

• No prior or concurrent radiotherapy for NSCLC

Surgery

• 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

Other

• 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neoadjuvant ZD1839 Preoperative Therapy; The ZD1839 250-mg tablet will be taken once a day, every day about the same time. It can be taken with or without food. At the time of surgery, investigators will collect tissue from the participant's tumor once it has been removed. This tissue will be used to study the effect of ZD1839 on tumor growth.	Drug: ZD1839; Other Names: gefitinib; IRESSA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	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.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Toxicity Related to Study Treatment	Review of adverse events utilizing Common Toxicity Criteria (CTC) V3. To estimate the safety, tolerability, and feasibility of preoperative ZD1839 in patients with resectable Stage IA/IB, II and selected IIIA NSCLC by evaluating toxicity and operability after preoperative ZD1839.	3 years

Collaborators and Investigators

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Collaborators: National Cancer Institute (NCI); AstraZeneca
• Investigators: Principal Investigator: Eric B. Haura, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study record dates

Study Major Dates

• Study Start: October 1, 2004
• Primary Completion (Actual): May 1, 2008
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: March 3, 2005
• First Submitted That Met QC Criteria: March 3, 2005
• First Posted (Estimate): March 4, 2005

Study Record Updates

• Last Update Posted (Estimate): October 31, 2012
• Last Update Submitted That Met QC Criteria: October 1, 2012
• Last Verified: September 1, 2012

More Information

Terms related to this study

• Keywords: stage IIIA non-small cell lung cancer; stage II non-small cell lung cancer; stage IA non-small cell lung cancer; stage IB non-small cell lung cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Gefitinib
• Other Study ID Numbers: MCC-13922; IRUSIRES0256 (Other Identifier: AstraZeneca)