Gefitinib in Treating Patients With Stage IB, II, or IIIA Non-small Cell Lung Cancer That Was Completely Removed by Surgery

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00049543
• Collaborator: (none)
• Enrollment: 503
• Location: 1
• Arms: 2
• Duration (Months): 103
• Patients Per Site Per Month: 4.9

Study Details

Study Description

Brief Summary

This randomized phase III trial studies how well gefitinib works in treating patients with stage IB, II, or IIIA non-small cell lung cancer that was completely removed by surgery. Gefitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known if gefitinib may be an effective treatment in preventing tumors from returning after they have been removed by surgery.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer	Drug: gefitinib; Other: placebo; Other: laboratory biomarker analysis	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. To assess, in comparison with placebo, the impact of adjuvant therapy with two years of daily oral ZD1839 (IRESSA) (gefitinib) on the overall survival of patients with completely resected (T1N1-2, T2N0-2, T3N0-2) non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

1. To compare the disease-free survival in the placebo arm to the ZD1839 (IRESSA) arm.

2. To confirm the prognostic significance of epidermal growth factor receptor (EGFR) expression, phosphorylation and mutations when present in the primary tumor.

3. To assess the ability of EGFR expression, phosphorylation and mutations in the primary tumor to predict the relative impact of ZD1839 (IRESSA) on survival.

4. To establish a comprehensive tumour bank linked to a clinical database for the further study of molecular markers in resected NSCLC.

5. To further evaluate toxicity related to ZD1839 (IRESSA).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive gefitinib orally (PO) once daily (QD) for 2 years in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO QD for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 6 months, every 6 months for 3 years, and then annually thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 503 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III Prospective Randomized, Double-Blind, Placebo-Controlled Trial of the Epidermal Growth Factor Receptor Antagonist, ZD1839 (IRESSA) in Completely Resected Primary Stage IB, II and IIIA Non-Small Cell Lung Cancer
• Study Start Date: Sep 1, 2002
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (gefitinib) Patients receive gefitinib PO QD for 2 years in the absence of disease progression or unacceptable toxicity.	Drug: gefitinib; Given PO; Other Names: Iressa ZD 1839 ; Other: laboratory biomarker analysis; Correlative studies
Placebo Comparator: Arm II (placebo) Patients receive placebo PO QD for 2 years in the absence of disease progression or unacceptable toxicity.	Other: placebo; Given PO; Other Names: PLCB ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Overall Survival [From randomization to the time of death from any cause, assessed up to 5 years]

   The survival experience of patients in both treatment groups will be described by the Kaplan-Meier method. A stratified log-rank test will be used as the primary method to compare the overall survival between two arms adjusting for the stratification factors. An unadjusted analysis will also be performed. Five years survival rate will be reported.

Secondary Outcome Measures

1. Disease Free Survival [From randomization to the time of documented recurrence of the primary cancer, assessed up to 5 years]

   The survival experience of patients in both treatment groups will be described by the Kaplan-Meier method. A stratified log-rank test will be used as the primary method to compare the disease free survival between two arms adjusting for the stratification factors. Five years disease free survival rate will be reported.

2. Incidence of Toxicities Graded Using the NCI Common Terminology Criteria for Adverse Events Version 3.0 [Up to 5 years]

   The incidence of toxicities will be summarized by type of adverse event and severity. A Fisher's exact test will be used to compare toxicities between the two arms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histological proof of a primary non-small cell lung cancer (bronchoalveolar carcinomas presenting as a discrete solitary radiological mass or nodule are eligible)

• Patients must be classified post-operatively as stage IB, II or IIIA on the basis of pathologic criteria

• At the time of resection a complete mediastinal lymph node resection or at least lymph node sampling should have been attempted; if a complete mediastinal lymph node resection or lymph node sampling was not undertaken, any mediastinal lymph node which measured 1.5 cm or more on the pre-surgical computed tomography (CT)/magnetic resonance imaging (MRI) scan or any area of increased uptake in the mediastinum on a pre-surgical positron emission tomography (PET) scan must have been biopsied; note: a pre-surgical PET scan is not mandatory

• The nodal tissue must be labelled according to the recommendations of the American Thoracic Society; surgeons are encouraged to dissect or sample all accessible nodal levels; the desirable levels for biopsy are:

• Right upper lobe: 4, 7, 10

• Right middle lobe: 4, 7, 10

• Right lower lobe: 4, 7, 9, 10

• Left upper lobe: 5, 6, 7, 10

• Left lower lobe: 7, 9, 10

• Surgery may consist of lobectomy, sleeve resection, bilobectomy or pneumonectomy as determined by the attending surgeon based on the intraoperative findings; patients who have had only segmentectomies or wedge resections are not eligible for this study; all gross disease must have been removed at the end of surgery; all surgical margins of resection must be negative for tumor

• No more than 16 weeks may have elapsed between surgery and randomization; for patients who received post-operative adjuvant platinum-based chemotherapy, no more than 26 weeks may have elapsed between surgery and randomization

• Patient must consent to provision of and investigator(s) must agree to submit a representative formalin fixed paraffin block of tumor tissue at the request of the Central Tumor Bank in order that the specific EGFR correlative marker assays may be conducted

• The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

• Leukocytes >= 3.0 x 10^9/L or >= 3000/ul

• Absolute granulocyte count >= 1.5 x 10^9/L or >= 1,500/ul

• Platelets >= 100 x 10^9/L or >= 100,000/ul

• Total bilirubin within normal institutional limits

• Alkaline phosphatase =< 2.5 x institutional upper limit of normal; if alkaline phosphatase is greater than the institutional upper limit of normal (UNL) but less than the maximum allowed, an abdominal (including liver) ultrasound, CT or MRI scan and a radionuclide bone scan must be performed prior to randomization to rule out metastatic disease; if the values are greater than the maximum allowed, patients will not be considered eligible regardless of findings on any supplementary imaging

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and/or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal; if AST (SGOT) or ALT (SGPT) are greater than the institutional upper limit of normal (UNL) but less than the maximum allowed, an abdominal (including liver) ultrasound, CT or MRI scan must be performed prior to randomization to rule out metastatic disease; if the values are greater than the maximum allowed, patients will not be considered eligible regardless of findings on any supplementary imaging

• Patient must have a chest x-ray done within 14 days prior to randomization; patient must have a CT or MRI scan of the chest done within 90 days prior to surgical resection if at least one of the following was undertaken:

• A complete mediastinal lymph node resection; or

• Biopsy of all desired levels of lymph nodes - as specified above; or

• A pre-surgical PET scan within 60 days prior to surgical resection If none of the above was undertaken then the CT or MRI scan of the chest must have been performed within 60 days prior to surgical resection Note: a pre-surgical PET scan is not mandatory

• Patient must have an electrocardiogram (EKG) done within 14 days prior to randomization

• Women of childbearing age and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and while taking study medication and for a period of three months after final dose; should a woman become pregnant or suspect she is pregnant while she or her male partner are participating in this study, she should inform her treating physician immediately

• Patients may receive post-operative radiation therapy; patients must have completed radiation at least 3 weeks prior to randomization and have recovered from all radiation-induced toxicity; patients who have received radiation therapy should also be randomized within 16 weeks of surgery

• Patient consent must be obtained according to local institutional and/or University Human Experimentation Committee requirements; it will be the responsibility of the local participating investigators to obtain the necessary local clearance, and to indicate in writing to either the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) study coordinator (for NCIC CTG centers) or the Cancer Trials Support Unit (CTSU) (for all other investigators), that such clearance has been obtained, before the trial can commence in that center; a standard consent form for the trial will not be provided, but a sample form is given; this sample consent form has been approved by the National Cancer Institute (NCI) Central Institutional Review Board (IRB) and must be used unaltered by those CTSI centers which operate under CIRB authority; for NCIC CTG centers, a copy of the initial full board Research Ethics Board (REB) approval and approved consent form must be sent to the NCIC CTG central office; please note that the consent form for this study must contain a statement which gives permission for the government agencies, NCI, NCIC CTG and monitoring agencies to review patient records

• NCIC-CTG Centers: the patient must have the ability to understand and the willingness to sign a written informed consent document; the patient must sign the consent form prior to randomization

• CTSU Centers: the patient, or in the case of a mentally incompetent patient his or her legally authorized and qualified representative, must have the ability to understand and the willingness to sign a written informed consent document; the consent form must be signed prior to randomization

• Patients must be accessible for treatment and follow-up; investigators must assure themselves that patients registered on this trial will be available for complete documentation of the treatment administered, toxicity and follow-up

• Initiation of protocol treatment must begin within 10 working days of patient randomization

• Patients may have received post-operative adjuvant platinum-based chemotherapy; patients must have completed chemotherapy at least 3 weeks prior to randomization and have recovered from all chemotherapy-induced toxicity; patients who have received adjuvant chemotherapy should also be randomized within 26 weeks of surgery

Exclusion Criteria:

• Prior or concurrent malignancies; patients who have had a previous diagnosis of cancer, if they remain free of recurrence and metastases five years or more following the end of treatment and, in the opinion of the treating physician do not have a substantial risk of recurrence of the prior malignancy, are eligible for the study; patients who have been adequately treated for non-melanomatous skin cancer or carcinoma in situ of the cervix are eligible irrespective of when that treatment was given

• A combination of small cell and non-small cell carcinomas or a pulmonary carcinoid tumor

• More than one discrete area of apparent primary cancer (even if within the same lobe, T4, IIIB)

• Clinically significant or untreated ophthalmologic (e.g. Sjogren's etc.) or gastrointestinal conditions (e.g. Crohn's disease, ulcerative colitis)

• Any active pathological condition that would render the protocol treatment dangerous such as: uncontrolled congestive heart failure, angina, or arrhythmias, active uncontrolled infection, or others

• A history of psychiatric or neurological disorder that would make the obtainment of informed consent problematic or that would limit compliance with study requirements

• Patient, if female, is pregnant or breast-feeding

• Neoadjuvant chemotherapy or immunotherapy for NSCLC; however, patients may have received pre-operative limited field, low dose (less than 1000 cGy) external beam radiation therapy or endobronchial brachytherapy or laser therapy for short term control of hemoptysis or lobar obstruction; full dose pre-operative radiotherapy of curative intent is a cause for exclusion; patients may have received post-operative adjuvant platinum-based chemotherapy however non-platinum-based chemotherapy is a cause for exclusion

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used on this trial; patients with ongoing use of phenytoin, carbamazepine, barbiturates, rifampicin, or St John's Wort are excluded

• Incomplete healing from previous oncologic or other major surgery

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Cancer Institute of Canada Clinical Trials Group	Kingston	Ontario	Canada	K7L 3N6

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Glennwood Goss, Canadian Cancer Trials Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00049543
• Other Study ID Numbers: NCI-2014-00650; NCI-2014-00650; SWOG-CAN-NCIC-BR19; ECOG-CAN-NCIC-BR19; BR19; CDR0000258118; CAN-NCIC-BR19; BR.19; BR.19; NCT00953069
• First Posted: Jan 27, 2003
• Last Update Posted: Jan 1, 2015
• Last Verified: Mar 1, 2014

• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Adenocarcinoma of Lung; Adenocarcinoma, Bronchiolo-Alveolar; Gefitinib

Study Results

Participant Flow

Arm/Group Title	Arm I (Gefitinib)	Arm II (Placebo)
Arm/Group Description	Patients receive gefitinib PO QD for 2 years in the absence of disease progression or unacceptable toxicity. gefitinib: Given PO laboratory biomarker analysis: Correlative studies	Patients receive placebo PO QD for 2 years in the absence of disease progression or unacceptable toxicity. placebo: Given PO laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	251	252
COMPLETED	249	243
NOT COMPLETED	2	9

Baseline Characteristics

Arm/Group Title	Arm I (Gefitinib)	Arm II (Placebo)	Total
Arm/Group Description	Patients receive gefitinib PO QD for 2 years in the absence of disease progression or unacceptable toxicity. gefitinib: Given PO laboratory biomarker analysis: Correlative studies	Patients receive placebo PO QD for 2 years in the absence of disease progression or unacceptable toxicity. placebo: Given PO laboratory biomarker analysis: Correlative studies	Total of all reporting groups
Overall Participants	251	252	503
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	105 41.8%	120 47.6%	225 44.7%
>=65 years	146 58.2%	132 52.4%	278 55.3%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	67.3	65.9	66.7
Sex: Female, Male (Count of Participants)
Female	116 46.2%	116 46%	232 46.1%
Male	135 53.8%	136 54%	271 53.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.8%	2 0.8%	4 0.8%
Asian	6 2.4%	3 1.2%	9 1.8%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.4%	1 0.2%
Black or African American	10 4%	9 3.6%	19 3.8%
White	233 92.8%	235 93.3%	468 93%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	2 0.8%	2 0.4%
Region of Enrollment (participants) [Number]
Canada	52 20.7%	50 19.8%	102 20.3%
United States	199 79.3%	202 80.2%	401 79.7%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	The survival experience of patients in both treatment groups will be described by the Kaplan-Meier method. A stratified log-rank test will be used as the primary method to compare the overall survival between two arms adjusting for the stratification factors. An unadjusted analysis will also be performed. Five years survival rate will be reported.
Time Frame	From randomization to the time of death from any cause, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Arm I (Gefitinib)	Arm II (Placebo)
Arm/Group Description	Patients receive gefitinib PO QD for 2 years in the absence of disease progression or unacceptable toxicity. gefitinib: Given PO laboratory biomarker analysis: Correlative studies	Patients receive placebo PO QD for 2 years in the absence of disease progression or unacceptable toxicity. placebo: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	251	252
Number (95% Confidence Interval) [percentage of 5 years survival rate]	0.52	0.57

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Gefitinib), Arm II (Placebo)
	Comments	The Kaplan-Meier estimates of survival distribution for overall survival by treatment arm are reported, and the log rank test stratified by the stratification factors at randomization (exclude center) was used to compare the difference in the overall survival between two treatment arms. Hazard ratio of comparison of study treatment arm to placebo and it 95% C.I. were reported.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 95%; 0.94 to 1.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Disease Free Survival
Description	The survival experience of patients in both treatment groups will be described by the Kaplan-Meier method. A stratified log-rank test will be used as the primary method to compare the disease free survival between two arms adjusting for the stratification factors. Five years disease free survival rate will be reported.
Time Frame	From randomization to the time of documented recurrence of the primary cancer, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Arm I (Gefitinib)	Arm II (Placebo)
Arm/Group Description	Patients receive gefitinib PO QD for 2 years in the absence of disease progression or unacceptable toxicity. gefitinib: Given PO laboratory biomarker analysis: Correlative studies	Patients receive placebo PO QD for 2 years in the absence of disease progression or unacceptable toxicity. placebo: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	251	252
Number (95% Confidence Interval) [percentage of 5-year disease free rate]	0.49	0.56

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Gefitinib), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments	Stratified by stratification factors at randomization (except center)
	Method	Log Rank
	Comments	Stratified by stratification factors at randomization (except center)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95%; 0.93 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Incidence of Toxicities Graded Using the NCI Common Terminology Criteria for Adverse Events Version 3.0
Description	The incidence of toxicities will be summarized by type of adverse event and severity. A Fisher's exact test will be used to compare toxicities between the two arms.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

All patients who received at least 1 dose of the treatment

Arm/Group Title	Arm I (Gefitinib)	Arm II (Placebo)
Arm/Group Description	Patients receive gefitinib PO QD for 2 years in the absence of disease progression or unacceptable toxicity. gefitinib: Given PO laboratory biomarker analysis: Correlative studies	Patients receive placebo PO QD for 2 years in the absence of disease progression or unacceptable toxicity. placebo: Given PO laboratory biomarker analysis: Correlative studies
Measure Participants	249	243
Number [participants]	229 91.2%	153 60.7%

Adverse Events

Arm/Group Title	Arm I (Gefitinib)		Arm II (Placebo)
Arm/Group Description	Patients receive gefitinib PO QD for 2 years in the absence of disease progression or unacceptable toxicity. gefitinib: Given PO laboratory biomarker analysis: Correlative studies		Patients receive placebo PO QD for 2 years in the absence of disease progression or unacceptable toxicity. placebo: Given PO laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Arm I (Gefitinib)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I (Gefitinib)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/249 (13.7%)		43/243 (17.7%)
Cardiac disorders
Cardiac General - Other	2/249 (0.8%)		4/243 (1.6%)
Cardiac ischemia/infarction	1/249 (0.4%)		1/243 (0.4%)
Left ventricular diastolic dysfunction	1/249 (0.4%)		0/243 (0%)
Left ventricular systolic dysfunction	1/249 (0.4%)		0/243 (0%)
Eye disorders
Blurred vision	1/249 (0.4%)		0/243 (0%)
Ocular - Other	1/249 (0.4%)		0/243 (0%)
Gastrointestinal disorders
Diarrhea	4/249 (1.6%)		2/243 (0.8%)
Dry mouth	1/249 (0.4%)		0/243 (0%)
Esophagitis	1/249 (0.4%)		0/243 (0%)
Fistula, GI Small bowel NOS	0/249 (0%)		1/243 (0.4%)
GI - Other	1/249 (0.4%)		1/243 (0.4%)
Gastritis	0/249 (0%)		1/243 (0.4%)
Heartburn	1/249 (0.4%)		1/243 (0.4%)
Hemorrhage, GI Colon	1/249 (0.4%)		0/243 (0%)
Hemorrhage, GI Lower GI NOS	1/249 (0.4%)		0/243 (0%)
Hemorrhage, GI Upper GI NOS	1/249 (0.4%)		0/243 (0%)
Nausea	2/249 (0.8%)		1/243 (0.4%)
Pain Abdomen NOS	1/249 (0.4%)		1/243 (0.4%)
Pancreatitis	2/249 (0.8%)		1/243 (0.4%)
Vomiting	2/249 (0.8%)		0/243 (0%)
General disorders
Constitutional Symptoms - Other	0/249 (0%)		2/243 (0.8%)
Death Disease progression NOS	1/249 (0.4%)		0/243 (0%)
Edema: limb	0/249 (0%)		2/243 (0.8%)
Fatigue	2/249 (0.8%)		1/243 (0.4%)
Fever	2/249 (0.8%)		1/243 (0.4%)
Pain - Other	1/249 (0.4%)		0/243 (0%)
Pain Chest/thorax NOS	0/249 (0%)		4/243 (1.6%)
Hepatobiliary disorders
Cholecystitis	0/249 (0%)		1/243 (0.4%)
Liver dysfunction	2/249 (0.8%)		0/243 (0%)
Immune system disorders
Allergic reaction	0/249 (0%)		1/243 (0.4%)
Infections and infestations
Infection - Other	4/249 (1.6%)		3/243 (1.2%)
Infection with normal ANC Lung	1/249 (0.4%)		1/243 (0.4%)
Infection with unknown ANC Lung	0/249 (0%)		2/243 (0.8%)
Injury, poisoning and procedural complications
Fracture	2/249 (0.8%)		0/243 (0%)
Investigations
ALT	0/249 (0%)		1/243 (0.4%)
AST	0/249 (0%)		1/243 (0.4%)
Creatinine	0/249 (0%)		1/243 (0.4%)
Weight gain	1/249 (0.4%)		0/243 (0%)
Weight loss	1/249 (0.4%)		0/243 (0%)
Metabolism and nutrition disorders
Acidosis	0/249 (0%)		1/243 (0.4%)
Dehydration	3/249 (1.2%)		2/243 (0.8%)
Hyperglycemia	0/249 (0%)		1/243 (0.4%)
Hyperkalemia	0/249 (0%)		1/243 (0.4%)
Musculoskeletal and connective tissue disorders
Arthritis	0/249 (0%)		1/243 (0.4%)
Pain Bone	0/249 (0%)		1/243 (0.4%)
Pain Extremity-limb	0/249 (0%)		1/243 (0.4%)
Pain Joint	1/249 (0.4%)		1/243 (0.4%)
Nervous system disorders
Ataxia	1/249 (0.4%)		0/243 (0%)
CNS hemorrhage	1/249 (0.4%)		0/243 (0%)
Dizziness	1/249 (0.4%)		1/243 (0.4%)
Encephalopathy	1/249 (0.4%)		0/243 (0%)
Neuropathy-sensory	1/249 (0.4%)		1/243 (0.4%)
Pain Head/headache	0/249 (0%)		1/243 (0.4%)
Seizure	1/249 (0.4%)		0/243 (0%)
Speech impairment	0/249 (0%)		1/243 (0.4%)
Syncope	0/249 (0%)		1/243 (0.4%)
Psychiatric disorders
Confusion	0/249 (0%)		2/243 (0.8%)
Mood alteration Anxiety	2/249 (0.8%)		2/243 (0.8%)
Mood alteration Depression	0/249 (0%)		1/243 (0.4%)
Psychosis	0/249 (0%)		1/243 (0.4%)
Renal and urinary disorders
Renal - Other	1/249 (0.4%)		1/243 (0.4%)
Renal failure	1/249 (0.4%)		1/243 (0.4%)
Respiratory, thoracic and mediastinal disorders
ARDS	1/249 (0.4%)		0/243 (0%)
Bronchospasm	0/249 (0%)		1/243 (0.4%)
Cough	2/249 (0.8%)		1/243 (0.4%)
Dyspnea	10/249 (4%)		14/243 (5.8%)
Fistula, pulmonary Lung	0/249 (0%)		1/243 (0.4%)
Hemorrhage pulmonary Lung	1/249 (0.4%)		0/243 (0%)
Hemorrhage pulmonary Respiratory tract NOS	0/249 (0%)		1/243 (0.4%)
Hypoxia	1/249 (0.4%)		0/243 (0%)
Pain Pleura	0/249 (0%)		1/243 (0.4%)
Pleural effusion	1/249 (0.4%)		1/243 (0.4%)
Pneumonitis	4/249 (1.6%)		3/243 (1.2%)
Pneumothorax	1/249 (0.4%)		0/243 (0%)
Pulmonary - Other	2/249 (0.8%)		1/243 (0.4%)
Pulmonary fibrosis	0/249 (0%)		1/243 (0.4%)
Skin and subcutaneous tissue disorders
Dry skin	1/249 (0.4%)		0/243 (0%)
Hand-foot	1/249 (0.4%)		0/243 (0%)
Pruritus	0/249 (0%)		2/243 (0.8%)
Rash	1/249 (0.4%)		0/243 (0%)
Vascular disorders
Hypertension	0/249 (0%)		1/243 (0.4%)
Hypotension	1/249 (0.4%)		1/243 (0.4%)
Peripheral arterial ischemia	0/249 (0%)		1/243 (0.4%)
Thrombosis/thrombus/embolism	4/249 (1.6%)		1/243 (0.4%)
Other (Not Including Serious) Adverse Events
	Arm I (Gefitinib)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	240/249 (96.4%)		226/243 (93%)
Gastrointestinal disorders
Constipation	39/249 (15.7%)		33/243 (13.6%)
Diarrhea	155/249 (62.2%)		75/243 (30.9%)
Heartburn	19/249 (7.6%)		20/243 (8.2%)
Nausea	66/249 (26.5%)		45/243 (18.5%)
Pain Abdomen NOS	18/249 (7.2%)		7/243 (2.9%)
Vomiting	32/249 (12.9%)		19/243 (7.8%)
General disorders
Edema: limb	11/249 (4.4%)		14/243 (5.8%)
Fatigue	135/249 (54.2%)		130/243 (53.5%)
Pain Chest/thorax NOS	86/249 (34.5%)		107/243 (44%)
Infections and infestations
Infection - Other	19/249 (7.6%)		20/243 (8.2%)
Investigations
ALT	13/249 (5.2%)		3/243 (1.2%)
AST	14/249 (5.6%)		2/243 (0.8%)
Weight loss	16/249 (6.4%)		6/243 (2.5%)
Metabolism and nutrition disorders
Anorexia	70/249 (28.1%)		40/243 (16.5%)
Hyperglycemia	26/249 (10.4%)		23/243 (9.5%)
Musculoskeletal and connective tissue disorders
Pain Back	13/249 (5.2%)		17/243 (7%)
Pain Bone	11/249 (4.4%)		15/243 (6.2%)
Pain Joint	14/249 (5.6%)		23/243 (9.5%)
Pain Muscle	12/249 (4.8%)		23/243 (9.5%)
Nervous system disorders
Dizziness	17/249 (6.8%)		17/243 (7%)
Neuropathy-sensory	26/249 (10.4%)		38/243 (15.6%)
Pain Head/headache	19/249 (7.6%)		15/243 (6.2%)
Psychiatric disorders
Insomnia	12/249 (4.8%)		19/243 (7.8%)
Mood alteration Anxiety	16/249 (6.4%)		11/243 (4.5%)
Mood alteration Depression	14/249 (5.6%)		14/243 (5.8%)
Respiratory, thoracic and mediastinal disorders
Cough	63/249 (25.3%)		71/243 (29.2%)
Dyspnea	130/249 (52.2%)		147/243 (60.5%)
Hemorrhage pulmonary Nose	16/249 (6.4%)		4/243 (1.6%)
Skin and subcutaneous tissue disorders
Acne	13/249 (5.2%)		1/243 (0.4%)
Alopecia	22/249 (8.8%)		14/243 (5.8%)
Dry skin	107/249 (43%)		46/243 (18.9%)
Nail changes	13/249 (5.2%)		4/243 (1.6%)
Pruritus	92/249 (36.9%)		32/243 (13.2%)
Rash	167/249 (67.1%)		66/243 (27.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.